Misuse and Abuse of Gabapentin.23 Because It Is Unclear If Gabapentin Is Being Abused in Utah, but Possible, the CSAC

Home , Gabapentinoid, Gabapentin enacarbil

UTAH MEDICAID DUR REPORT JANUARY 2020

ABUSE AND MISUSE OF GABAPENTIN

Drug Regimen Review Center Joanita Lake B.Pharm, MSc EBHC (Oxon), Research Assistant Professor Lauren Heath, Pharm.D., MS, BCACP, Assistant Professor (Clinical) Valerie Gonzales, Pharm.D., Clinical Pharmacist Vicki Frydrych, B.Pharm., Pharm.D., Clinical Pharmacist Elena Martinez Alonso, B.Pharm., MSc MTSI, Medical Writer Stephen Kim, Pharm.D. student Angela Clayton, Pharm.D. student Joanne LaFleur, Pharm.D., MSPH, Associate Professor

Data support Jacob Crook, MStat

Acknowledgement We acknowledge, with thanks, The Utah Poison Control Center (UPCC), and Executive Director of UPCC; Barbara Insley Crouch Pharm D, MSPH for the gabapentin exposures and reports that were created for inclusion in this report.

Introduction ...... 4 Background ...... 5 Methodology ...... 6 Gabapentin pharmacokinetics (vs pregabalin) ...... 7 Gabapentin dosage ...... 7 Safety ...... 8 Centers for Disease Control and Prevention (CDC) ...... 8 National Vital Statistics Reports: Regional Differences in the Drugs Most Frequently Involved in Drug Overdose Deaths: United States, 2017 ...... 8 Utah Poison Control Center (UPCC) ...... 10 Drug Abuse Warning Network (DAWN) ...... 11 Factors that may increase risk of adverse events/abuse ...... 11 Off-label use ...... 11 Systematic reviews of abuse or misuse ...... 13 Studies in Utah ...... 14 Factors and limitations to consider ...... 14 Utah Medicaid Utilization Data ...... 17 A. Overall total utilization of gabapentin (2016-2019) ...... 17 B. Most commonly used gabapentin formulations (2016-2019) ...... 18 C. Age and gender (2016-2019) for ALL and FFS groups ...... 19 D. Diagnoses (FFS all age groups) ...... 21 E. Pediatric patients ...... 21 F. Prescribers of gabapentin (FFS) ...... 22 G. Doses ...... 23 H. Long-term users (>12 months) (2016-2019) ...... 25 I. Additional potential problematic use data ...... 26 Conclusions ...... 28 Appendix 1 – Drug information ...... 29 Table 1. Summary of Gabapentin Dosing Recommendations ...... 29 Appendix 2 – Search strategy ...... 31 Figure 1 – PRISMA flowchart ...... 33 Appendix 3 – Systematic review evidence ...... 34 Table 1. The Problem: Gabapentin abuse data from systematic reviews ...... 34

Table 2. Targets for interventions: Gabapentin abuse data from systematic reviews ...... 39 Table 3. Implications of lack of or failed interventions (to prevent abuse and adverse consequences): Gabapentin abuse data from systematic reviews ...... 43 Appendix 4 – Utah Poison Control Center: Gabapentin exposures ...... 44 Appendix 5 - Additional data ...... 47 Table 1. All claims ...... 47 Table 2. FFS claims ...... 47 Table 3. Pediatric claims ...... 48 Table 4. Number of pediatric patients by age and diagnosis codes ...... 49 Table 5. Diagnosis codes submitted (adult and pediatric patients) ...... 51 Table 6. Prescribers ...... 52 Appendix 6 – Exploring potential problematic use ...... 54 Table 1. Number of patients (ALL) by number of prescriptions (in last year) with select diagnoses ..... 54 Table 2. Number of patients (ALL) by number of prescriptions (in last year) that fulfil select criteria.. 55 Table 3. Number of patients (FFS) by number of prescriptions (in last year) with select diagnoses ..... 57 Table 4. Number of patients (FFS) by number of prescriptions (in last year) that fulfil select criteria .. 58 Table 5. Prescribers of patients with >400 days’ supplied from Oct 1, 2018 - Sep 30, 2019 ...... 59 Table 6. Diagnosis codes submitted for potential inappropriate gabapentin use/prescribing/patients at increased risk for adverse outcomes ...... 60 References ...... 61

Introduction

Drug overdose is the leading cause of accidental death in the US (70,237 drug overdose deaths occurred in the United States in 2017) and of these 67.8% of deaths are related to opioids.1,2 The most recent emergency department data from the fourth quarter of 2017 to the fourth quarter of 2018 show Utah is one of five states with significant increases in all suspected drug overdoses.3 Drugs other than opioids contribute to the alarming number of overdoses.3 Frequently, several drugs are involved in overdose cases and the contribution of each drug to the person’s death cannot be determined from the literal text analysis of death certificates.4,5 The role of gabapentin in the drug overdose epidemic is unclear.

In an effort to curb opioid use, the Centers for Disease Control and Prevention (CDC) Guideline for Prescribing Opioids for Chronic Pain recommends nonpharmacologic therapy and nonopioid pharmacologic therapy as preferred for the treatment of chronic pain and that opioid use is considered only if “expected benefits for both pain and function are anticipated to outweigh risks to the patient.”6 They also recommend combining opioids (if used) with nonpharmacologic therapy and nonopioid pharmacologic therapy, as appropriate (recommendation category: A, evidence type: 3).6 Chronic pain refers to pain lasting more than 3 months or past the time of normal tissue healing.6 Also, these recommendations are not intended for pain during active cancer treatment, palliative care, or end-of- life care.6 The CDC states that “[c]ontinued efforts to ensure safe prescribing practices by following the CDC Guideline for Prescribing Opioids for Chronic Pain are enhanced by access to nonopioid and nonpharmacologic treatments for pain.”2 However, the CDC cautions against aggressive implementation of the guideline (e.g., immediate and aggressive opioid tapering) due to the potential for patient harm.7

Gabapentin was previously thought to not have abuse potential, but evidence to the contrary is emerging. Restricting opioid prescribing, and encouraging nonopioid treatments for pain, may be facilitating increases in gabapentin prescriptions and abuse. The Drug Enforcement Administration (DEA) reported an increase in problematic gabapentin use in recent years.8 It has been “…increasingly encountered by law enforcement, documented in national crime lab reports, reported to poison control centers, and diverted for illicit use.”8 Gabapentin may be misused for recreational use (to get “high” or increase a “high” when taken with opioids or other medications), self‐medication (for pain or withdrawal symptoms), or self-harm (suicide).9 In 2017, there were 6,722,145 prescriptions (IMS HealthTM) dispensed for gabapentin in the US which has doubled since 2011.8 More patients are being exposed to gabapentin, frequently for off-label use, increasing the risk of gabapentin abuse. Possible reasons for the increasing use and abuse include the ease of obtaining prescriptions for large quantities and low cost (it has been referred to as a ‘cheap man’s high’9).10 Several other factors also increase this risk of abuse such as misunderstandings of abuse potential amongst prescribers.10

The main focus of this review is the safety and appropriate use of gabapentin. We aim to:

(A) Review evidence of gabapentin misuse and abuse worldwide, and in Utah specifically, to determine the extent of the problem including the following: a) Prevalence b) Populations at increased risk for abuse/misuse c) Sources of abused or misused gabapentin, and street market d) Doses needed for effects sought by abusers or misusers e) Toxic effects, drug overdoses, and management of intoxication f) Factors increasing the abuse effect/risk of overdose

(B) Review product information, tertiary data sources (electronic databases e.g., Micromedex, Lexicomp), and other sources of expert information for information regarding FDA-labeled indications and select drug-drug interactions, including both pharmacokinetic and pharmacodynamic issues.

We will not be reviewing the appropriateness of off-label uses including use in the treatment of substance use disorder, but information will be included to explain its place in therapy.

(C) Review national and local (Utah) data and statistics (e.g., CDC and Poison Control exposure data) to provide further insight into gabapentin use in Utah.

(D) Review gabapentin utilization in the Utah Medicaid population to determine whether potentially inappropriate use is a problem

Ultimately, the purpose of this review is to help reduce inappropriate use and prescribing (if it is a problem).

Background

Gabapentin is FDA-approved as adjunctive therapy in the treatment of epilepsy (partial onset seizures, with and without secondary generalization) in patients >3 years old, and for the treatment of postherpetic neuralgia in adults.11 Gabapentin enacarbil extended release tablets (Horizant) is indicated for treatment of moderate-to-severe restless leg syndrome (RLS) and postherpetic neuralgia (PHN) in adults.12 Other uses of gabapentin are off-label. Some off-label indications are with supportive evidence and clinical guidelines recommending their use (neuropathic pain, post-operative pain, alcohol use disorder, chronic refractory cough, and migraines, to name a few).12,13 Gabapentin is structurally related to pregabalin (a schedule V drug) in that they both contain GABA, but gabapentin has a lipophilic cyclohexyl group attached to GABA.8 Gabapentin has analgesic and antiepileptic actions, but its exact mechanism of action is unknown.8

Gabapentin does not bind to GABAA, GABAB, opioid, benzodiazepine or cannabinoid receptors (at clinically therapeutic doses of 900-3600 mg/day) although it can increase GABA levels (dose- dependently with a modest increase of extracellular GABA in brain14) and decrease glutamate concentrations.15,8,16,17 Because of this, the gabapentin drug approval process did not require abuse- potential assessment and it is not currently controlled under the Federal Controlled Substances Act of 1970. Gabapentin is not a controlled substance in most states. The exact mechanism of gabapentinoid abuse is not fully understood,10 but it is thought to be related to the weak GABAmimetic activity which may cause relaxation and euphoria, especially at the beginning of therapy and during an overdose.14 Usually increases in dopamine plays a role in the addictive power of drugs, and according to authors of a recently published systematic review, there is currently no evidence indicating gabapentinoids may cause this action in the mesolimbic reward system.14 However, they state that neuroimaging studies to evaluate this are warranted.14 Nonetheless, due to increases in prescribing and abuse, it has been classified as a Schedule V controlled substance at a state level (not federal level) in Kentucky (July 2017), Tennessee (July 2018), Michigan (January 2019), and Alabama (November 2019), with more states considering this change.18-22 In Utah, the Board of Pharmacy requested the Controlled Substances Advisory Committee (CSAC) to consider a recommendation to schedule gabapentin in the Utah Controlled Substances Act as a Schedule V controlled drug based on national trends in the misuse and abuse of gabapentin.23 Because it is unclear if gabapentin is being abused in Utah, but possible, the CSAC

2019 Legislative Recommendations to the Members of the Health and Human Services (HHS) Interim Committee was that gabapentin dispensing data be required for the controlled substances database, and evaluated to determine if it should be scheduled as a controlled substance next year (2020 legislative session).23 Since December 2016, Ohio required gabapentin data be entered into their Ohio Automated Rx Reporting System (OARRS).24 In December 2017, Ohio implemented a rule that requires prescribers to include the days’ supply (ie, minimum number of days) that the prescription for a controlled substance (CS) or gabapentin should last the patient.25 It appears that there is a rule allowing processing of a prescription without this information, but the pharmacy has to follow requirements for reporting days’ supply.25

This is not the first drug that was thought to have no abuse potential until much later after approval.10 The abuse potential of benzodiazepines and Z-hypnotics also took several years to be fully appreciated.10,26 This may have resulted from trials excluding patients with substance use disorders that could have signaled this risk.10,27,28 Some experts suggest that perhaps abuse liability-focused premarketing studies should consider interaction with alcohol and other drugs as well as routine postmarketing surveillance to assess abuse potential of all new drugs with central nervous system (CNS) activity.26,29-31

Methodology

A literature search was developed to identify all systematic reviews and meta-analyses worldwide that reported gabapentin misuse and/or abuse in any population. We also searched for Drug Enforcement Administration (DEA) Drug and Chemical evaluations, and any publication types providing information specific to Utah. We searched Pubmed, Epistemonikos, the DEA website, and the CDC website in November 2019. The Pubmed Medline and Epistemonikos search strategies are included in the supplementary appendix. Search strategies consisted of controlled vocabulary, such as medical subject headings (i.e., MeSH and EMTREE terms), in combination with text words. Search terms were gabapentin AND (abuse OR misuse OR non-medical or nonmedical OR illicit OR addict OR addiction OR diversion OR dependence OR drug-seeker OR drug-seeking OR trafficking OR inappropriate OR overprescribing OR overprescriber or overprescribers OR overtreating OR overdiagnosis OR high). Systematic reviews search filters from Pubmed32 and adapted by Dalhousie university libraries33 from SIGN34 were used. We searched the FDA website, the Substance Abuse and Mental Health Services Administration (SAMHSA) website, University of Maryland Center for Substance Abuse Research (CESAR) website,35 Micromedex, and Lexicomp. No language limits were applied.

Results were uploaded into Covidence,36 and following the removal of duplicates, titles and abstracts were screened independently by 2 reviewers. Data was extracted on gabapentin misuse, and abuse.

(1) In order to determine the nature of the problem, its magnitude and who is best placed to deal with the problem. Information was extracted on (a) prevalence of gabapentin misuse or abuse, (b) sources of gabapentin in the context of misuse/abuse, (c) drug effect sought/reason for abuse, (d) toxic/clinical presentation, and (d) overdoses.

(2) Information was also collected to help inform intervention strategies for who to target and potentially to review problem doses and consider dosage restrictions if appropriate including (a) populations at increased risk for misuse or abuse, (b) doses needed for abuse-related effects, and (c) factors increasing the abuse effect or risk for overdose/death.

(3) In order to determine the implications of lack of or failed interventions (to prevent abuse and adverse consequences), information was collected on management of intoxication, and about the cost associated with overdose (eg, hospitalizations).

We searched Pubmed for any studies in Utah about gabapentin misuse or abuse.

Human exposures to gabapentin reported to the Utah Poison Control Center between January 1, 2014 and September 30, 2019 were reviewed and a summary of cases were presented if the exposure involved gabapentin in patients of all ages, and for any reason for exposure.

Utilization data in the Utah Medicaid population was extracted.

Gabapentin pharmacokinetics (vs pregabalin)

Gabapentin has unpredictable pharmacokinetics and non‐linear bioavailability.9,37 Its systemic absorption is slow (peak plasma level within 3-4 hours)38 and has low bioavailability (25-50%) compared to pregabalin (≥90%).37 Gabapentin bioavailability varies by the dose administered e.g., 68% after a 300 mg dose vs 36% after a 1600 mg dose.10,27,39 Because of pregabalin’s quicker absorption, higher potency by 2.5-6 times higher, faster onset of action, faster plasma peak concentration by 3-fold, and higher bioavailability (>90%), it may be preferred for abuse purposes over gabapentin and may be more addictive..10,26,27,37-40 A review of the European Medicines Agency (EMA) EudraVigilance (EV) database over the last decade showed more misuse-related adverse events for pregabalin compared to gabapentin.26,41 Schifano et al state this confirms pregabalin’s higher addictive liability.14,26,41 Likewise, Bonnet and Scherbaum reached similar conclusions given pregabalin use was more frequently associated with behavioral dependence, and switches from prescription to self-administration.14 Medications that slow gastrointestinal motility prolong the transit time of gabapentin in the small intestine and could potentially enhance the absorption and bioavailability of gabapentin.37 In one study bioavailability increased by 50% when a 600 mg gabapentin dose was coadministered with oral morphine.37,42 Gabapentin is excreted renally, without hepatic metabolism and with an excretion half- life of approximately 6 hours.38

Gabapentin enacarbil is a prodrug of gabapentin (hydrolyzed primarily in the intestines to gabapentin).43 Gabapentin enacarbil (Horizant) and other gabapentin products are not interchangeable due to differences in formulation and pharmacokinetics and differences in approved indications.43,44

Gabapentin dosage

Appendix 1 contains dosage information for gabapentin, including maximum daily doses, with respect to indications, based on the FDA prescribing information and clinical guidelines. However, the effects and experiences of users (e.g. euphoria, increased energy, sedation, and dissociation) are more likely at higher doses, but can occur at any dose.9

Doses above 3600 mg/day regardless of indication appear inappropriate (See Table 1 of Appendix 1). There is a limited evidence to suggest therapeutic benefit from doses >3600mg for any indication (off- label included) of gabapentin. Higher doses are associated with more adverse effects (nausea,

7 somnolence) and abuse or misuse.10 Since gabapentin has also been abused even at therapeutic doses, it is important to identify other potential indicators of abuse or misuse such as a pattern of very early refills (eg. more than 5 days before the previous supply runs out) and diagnoses for drug abuse.

Pediatric patients and patients with renal impairment require lower doses.12

Safety

Serious adverse effects with gabapentin include dizziness, somnolence, psychiatric reactions (thought disorder and disturbances, hostile behavior hyperactive behavior, mood swings, and suicidal thoughts) and others like immunologic reactions, hypoglycemia, and angioedema. Other common adverse effects include peripheral edema, ataxia (incoordination), fatigue and nystagmus (involuntary rapid eye movement).8,45

Reports and studies are emerging indicating that gabapentin, similar to pregabalin, is associated with effects often sought by drug abusers including sedative and/or psychedelic effects.8

Dose reductions are required in patients with renal insufficiency. Gabapentin is pregnancy risk factor C. It is present in breast milk and the risk versus benefit should be considered. Pregnancy registry outcome data following use during pregnancy and/or breastfeeding information is limited.12,43

In general, concomitant use of gabapentin with opioids and benzodiazepines or other CNS depressants should be avoided when possible, because of the risk of additive toxicity (adverse/toxic effects). These agents should only be combined if alternative treatment options are inadequate, and if combined, dosages and duration of each drug should be limited. Alcohol should be avoided with the use of the long-acting formulation, because the rate of absorption may be enhanced (increased release of drug).43

Centers for Disease Control and Prevention (CDC)

National Vital Statistics Reports: Regional Differences in the Drugs Most Frequently Involved in Drug Overdose Deaths: United States, 2017

It is important to consider the following information in the context of the limitations reported by the authors which included jurisdiction and time variations in death investigations and reporting practices, or medicolegal death investigation systems. This includes whether toxicological laboratory testing is performed to determine the type(s) of drugs present, substances tested for and the circumstances under which the tests are performed, resource factors (office staffing and personnel, caseload, budget, and availability of specific toxicology tests), interpretation of findings, potential misattribution of drugs, and decisions about which drugs to report on death certificates. The authors state that routine toxicological analysis can range from no testing at all, to urine screening with no further confirmation, to complete quantification of all potential toxins involved. Medical certifiers may include a single lethal drug and not multiple drugs involved or they may not want to impose an order when listing drugs.46 Nevertheless, at least one drug or drug class was reported on the death certificate for 87.6% of drug overdose deaths in 2017, but this varied by region, nationally, between 75.4% and 98.9%.46 The authors did conduct an adjustment analysis, and cautioned readers to consider the variation in the specificity of drug reporting by region when reviewing the results.46 Also, multiple drugs are frequently involved in

8 overdose deaths and the authors state that the contribution of each drug to the death cannot be determined from the literal text analysis; this limitation should be considered.4,5,46

Gabapentin was amongst the top 15 drugs most frequently involved in drug overdose deaths in the United States in 2017; however, its involvement is much lower compared to other drugs such as fentanyl, heroin, cocaine, and methamphetamine.46 Nationally in 2017, 2.6% of drug overdose deaths involved gabapentin compared to 38.9% involving fentanyl, 22.8% heroin, 21.3% cocaine, and 13.3% methamphetamine, and 6.9%–9.5% alprazolam, oxycodone, and morphine (each). The national age- adjusted rate, where gabapentin was found in persons with overdose, was 0.6 per 100,000 standard population; for region 8, with Utah, the age-adjusted rate was 1.6 per 100,000. Similarly methadone, hydrocodone, diphenhydramine, clonazepam, diazepam, amphetamine, and tramadol were each involved in less than 5.0% of drug overdose deaths.46 Fentanyl remains the drug most frequently involved in drug overdose deaths in the United States (27,299/70,237= 39% of overdose deaths; age- adjusted rate of 8.7 per 100,000 vs. 29% in 2016; age-adjusted death rate of 5.9 per 100,000).46

Direct excerpt from report46

Gabapentin ranked among the top 10 most frequent drugs involved in drug overdose deaths in only one region (region 4). The top 10 most frequent drugs involved in drug overdose deaths in region 8 (Utah’s region) are shown in table B below, from the report In Utah’s region, the drug most commonly identified in overdose deaths was methamphetamine (28.7%), followed by heroin (21.2%) and oxycodone (16.2%). Gabapentin was not among the top 10 drugs identified among drug overdose deaths in region 8.

Direct excerpt from Table B of the report.46

Utah Poison Control Center (UPCC)

Utah Poison Control Center (UPCC) is one of 55 poison control centers serving the US (330 million people).47 Appendix 4 contains a summary of cases over the last 5 years involving gabapentin from the UPCC. There were a total of 2,011 cases that involved gabapentin between January 1, 2014 and September 30, 2019, which is about 1% of the total UPCC human exposures. Almost two thirds of the gabapentin cases (62.2%) were due to intentional ingestion. The percentage gabapentin contributed to the total intentional exposures has increased from 3.2% in 2014 to 4.5% in 2019 (data for 2019 only until September 30). Intentional abuse and misuse overall constituted a small portion of the intentional cases (3.5% and 5.6% respectively) with suicide being the main category of intentional cases (50.4%). Suicide attempt as a reason for gabapentin exposure was documented in children as young as 6-12 years of age. It was the reason for the majority of cases in the 13-19 years of age category, as well as the most common intentional cause in adults. The majority of exposures were in adults (≥20 years of age; 80.71%) and there were slightly more female exposures (59.32%). Exposures in children ≤5 years of age accounted for approximately 10% of cases.

Of the total gabapentin exposures, most exposures (89.9%) occurred at a residence and slightly more than half of consults originated from a healthcare facility. Slightly more than two thirds of all exposures (68.3%) were managed in a healthcare facility with 22.8% treated and released from emergency departments, 15.6% admitted to critical care units, 10.5% to a noncritical care unit, and 15.5% to a psychiatric facility. Over the last 5 years, there were 91 (4.5% of the total gabapentin exposures) major effect outcomes and 3 deaths (0.2% of the total gabapentin exposures). Several other substances were documented concomitantly in gabapentin case records including ethanol, analgesics, anticonvulsants, antidepressants, antihistamines, cardiovascular drugs, muscle relaxants, hormones, sedative hypnotics/antipsychotic agents, and stimulants/street drugs. Documentation of analgesics, antidepressants, and sedative hypnotics/antipsychotic agents appear more frequently (please refer to appendix 4 for additional information).

Drug Abuse Warning Network (DAWN)

Until 2011, DAWN produced estimates of drug-related emergency department visits.48 ED visit rates (per 100,000 population) for gabapentin increased from 2.7 in 2004 to 4.9 in 2011.8 SAMHSA is re- establishing the DAWN surveillance system on a smaller scale with improved timeliness of data (‘early warning’ system) and data abstraction will begin in mid-2019.48

Factors that may increase risk of adverse events/abuse

 Patients with a history of substance abuse: A history of or current drug abuse, particularly opioids, appears to be a risk factor for gabapentin misuse.9  High doses: Doses exceeding recommended doses increase the risk of adverse events without offering any additional treatment benefit. Appendix 1 contains dosage information on gabapentin by indication, based on the FDA prescribing information and clinical guidelines. The majority of case reports of misused gabapentin involved prescribed gabapentin where patients took higher doses than prescribed doses.9 Unlike some other drugs of abuse, users develop tolerance to the euphoric high of gabapentin14 which is “…suggested to drive a considerable overdosing.”14,49,50 Bonnet and Scherbaum state that that the toxicity profile of gabapentinoids is controversial.14  Extended treatment periods/ Long-term use: Long-term use could lead to dependence, withdrawal on discontinuation, and a prolonged risk for adverse events including dangerous drug interactions (i.e., CNS depression with opioids). Nonetheless, the benefits may outweigh these risks for many patients. It may also increase the amount of gabapentin available for diversion and abuse.  Concomitant opioid and gabapentin: Gomes et al (large study; >16 years) found a substantial increase (49%) in the risk of opioid-related death in patients receiving concomitant opioid and gabapentin treatment.51 Also, moderate (900 to 1,799 mg daily) or high dose (1,800 mg daily or more) was associated with a nearly 60% increased odds of opioid-related death compared to exposure to opioids alone (secondary analysis), and a very high dose (2,500 mg daily or more) of gabapentin was associated with a nearly 2-fold increased odds of opioid-related death (post-hoc analysis). Low gabapentin dose (<900 mg daily), was not significantly associated with an increased odds of opioid-related death.51  Multiple CNS drugs e.g. patients using more than one drug causing CNS depression.  Patients whose job or lifestyle requires unimpaired intellectual or psychomotor function

Off-label use

Gabapentin is being used off-label for a variety of conditions (estimated to be 83-95% if its use), some which have supportive evidence and are recommended by clinical practice guidelines. Nonetheless, because its exact mechanism is unclear and the medication in the past had been regarded as having no abuse potential (ie, non-controlled status), prescribing rates may have expanded more rapidly compared to if the drug was regarded as a controlled substance with abuse potential.9,52,53 There is insufficient evidence or no current evidence to support the use of gabapentin as treatment in patients with substance use disorder (misuse/abuse/dependence other than alcohol).13,54-62 Off-label uses of gabapentin supported by guidelines include the following:  moderate to severe alcohol use disorder (APA63 and VADoD64; level B evidence)

 alternative agent for alcohol withdrawal when the risk of benzodiazepines outweigh the benefit (VADoD64; level B evidence)  alternative agent for chronic refractory cough (ACCP65; level C evidence),  neuropathic pain other than postherpetic neuralgia (ie, peripheral neuropathy, diabetic neuropathy (IASP,66 EFNS,67 SCCM,68 NICE,69 AAN,70 ADA71; level A evidence),  postoperative pain as part of a perioperative multimodal analgesia regimen to decrease postoperative pain and opioid use (American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists’ Committee on Regional Anesthesia, Executive Committee, and Administrative Council;72 level B),  chronic pruritus of neuropathic origin or malignancy related, and uremic pruritis (chronic kidney disease-associated pruritus) (European Dermatology Forum (EDF) and European Academy of Dermatology and Venerology (EADV) guidelines;73 level C and B, respectively),  alternative for vasomotor symptoms (hot flashes) in postmenopausal women and breast cancer survivors (American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) position statement on menopause,74 the Endocrine Society (ES) guideline on treatment of symptoms of menopause,75 and the North American Menopause Society (NAMS) position statement on nonhormonal management of menopause-associated vasomotor symptoms,76 American Cancer Society/American Society of Clinical Oncology (ACS/ASCO) breast cancer survivorship care guideline;77 level B),  restless leg syndrome (gabapentin enacarbil is FDA-approved for this indication) (The American Academy of Sleep Medicine (AASM) guidelines regarding RLS management,78 The European Federation of Neurological Societies/European Neurological Society/European Sleep Research Society (EFNS/ENS/ESRS) Task Force guidelines,79 the International Restless Legs Syndrome Study Group, European Restless Legs Syndrome Study Group, and RLS Foundation (IRLSSG/EURLSSG/RLS-F) guidelines for the prevention and treatment of dopaminergic augmentation in restless legs syndrome;80 level B).12

Because restless legs syndrome (RLS)/Willis-Ekbom disease (WED) is common during pregnancy (affecting approximately one in five pregnant women), a task force chosen by the International RLS Study Group (IRLSSG) developed guidelines for the diagnosis and treatment of RLS/WED during pregnancy and lactation.81 These guidelines state that there is insufficient evidence to recommend gabapentin use in pregnant women for restless leg syndrome (off-label use), and that gabapentin may be considered for the treatment of refractory restless leg syndrome in breastfeeding women (Picchietti 2015).12,43 Even though gabapentin may be used for moderate to severe alcohol use disorder in certain situations (APA63 and VADoD64; level B evidence), APA guidelines state that pharmacological agents should not be used for the treatment of alcohol use disorder in pregnant or breastfeeding women unless needed for the treatment of acute alcohol withdrawal or a coexisting disorder.12,43,63,81

Off-label uses in Lexicomp without guideline recommendations (may need additional evidence) include fibromyalgia (level B), persistent or intractable hiccups (singultus) (level C), and social anxiety disorder as an adjunct to antidepressants or monotherapy (alternative agent) (level C).12

Please refer to guidelines for details and specifics of recommendations.

Definitions of levels of evidence: “A - Consistent evidence from well-performed randomized, controlled trials or overwhelming evidence of some other form (eg, results of the introduction of penicillin treatment) to support the off-label use. Further research is unlikely to change confidence in the estimate of benefit. B - Evidence from randomized, controlled trials with important limitations (inconsistent results, methodological flaws, indirect or imprecise), or very strong evidence of some other research design. Further research (if performed) is likely to have an impact on confidence in the estimate of benefit and risk and may change the estimate. C - Evidence from observational studies (eg, retrospective case series/reports providing significant impact on patient care), unsystematic clinical experience, or from potentially flawed randomized, controlled trials (eg, when limited options exist for condition). Any estimate of effect is uncertain. G - Use has been substantiated by inclusion in at least one evidence-based or consensus-based clinical practice guideline.”43

Systematic reviews of abuse or misuse

Appendix 3 contains evidence from the included systematic reviews.

In the general population the prevalence of gabapentin abuse appears low (~1%). Current or past substance abusers particularly opioids (15-22%), but also benzodiazepine, cocaine, cannabis, heroin, and other illicit drug users, appear to be at increased risk for gabapentin abuse. Other populations at increased risk for misuse or abuse of gabapentin include patients with psychiatric comorbidities, patients that are suicidal, patients that are vulnerable to the increased ‘pro-drug’ information on the web like children/adolescents, and inmates. More patients prescribed gabapentin abuse it compared to those without a prescription. Prescriptions appear to be a major source of the abused/misused gabapentin. Reasons for abuse include to “get high” (whilst producing only few side-effects), to potentiate methadone high or buprenorphine/naloxone effect, to avoid detection during urine drug screening, used as a cutting agent for heroin, substitute for cocaine, to alleviate opioid withdrawal symptoms, self-medication of uncontrolled pain, anxiety, or withdrawal of other drugs/minimize cravings, and intentional self-harm. Toxic effects include various such as CNS symptoms and psychedelic effects. It is controversial how toxic gabapentin is on its own. It is often taken in combination with other drugs. Overdoses, and data from post-mortem toxicology analyses have been included in table 1 (appendix 3). Doses needed for abuse-related effects include therapeutic doses, and supratherapeutic doses. Patients may be taking usual doses as a single dose so it may not always be evident from prescriptions when it is being misused. Factors increasing the abuse effect or risk for overdose/death include concurrent use with other drugs such as opioids and other CNS depressants, high doses, administration via other non-oral routes, and access because it is not controlled. Not much is reported in these systematic reviews for management of gabapentin intoxication, apart from the case reports. Some report that it is relatively safe even following acute overdose, that outcomes are generally mild- moderate, and resolved within 10 hours in case series. Outcomes may be more severe when taken with other drugs and with renal impairment. None of the systematic reviews included information on the cost associated with overdose.9,10,14,38,49,82

Bonnet and Scherbaum state that the assumption that gabapentinoids are being abused (because it if easily obtainable) corresponds to pharmacoepidemiological analyses of prescription data and spontaneous reports to pharmacovigilance databases (mainly Scandinavia, UK, and Germany).14 However, they also note that it could just be that gabapentinoids are “innocent bystanders of other

13 more powerful substance use disorders (SUD).”14 They reviewed the gabapentinoids’ addiction risk and did not find sufficient evidence “of a vigorous addictive power of gabapentinoids” or for people seeking treatment for gabapentinoid use disorder. In patients without a prior abuse history, there were very few cases of dependence symptoms i.e. “wanting” (N=4) and these were for pregabalin and not gabapentin. Patients with current or past substance use disorders (mostly opioid and multi-drug users) appeared to be at risk for abuse of gabapentinoids. When taken on its own in overdose, gabapentinoids appeared safe, but the risk for lethal outcomes increased when taken with other drugs especially opioids and sedatives. The authors recommend “in patients with a history of SUD, gabapentinoids should be avoided or if indispensable, administered with caution by using a strict therapeutic and prescription monitoring.”14

Limitations of current evidence include inherent bias of studies (study designs include retrospective reviews, survey data, and case reports), publication bias (more publications since the abuse issue received more attention), literature searches of the included systematic reviews were not comprehensive, inconsistent data reporting and insufficient description of the included studies of some systematic reviews, insufficient risk of bias assessment in the systematic reviews, lack of reporting of funding sources of included studies in systematic reviews, generalizability (e.g., to other countries), and combined reporting of gabapentin and pregabalin in some cases (effects may be different). 9,10,14,38,49,82

Studies in Utah

No studies were identified for gabapentin misuse or abuse in Utah. The single study that was identified was excluded, because it was not about abuse or misuse. It describes an assay to support therapeutic drug monitoring of gabapentin and levetiracetam in plasma.83

Factors and limitations to consider

 CDC: In an effort to resolve the drug overdose epidemic, CDC developed and published the CDC Guideline for Prescribing Opioids for Chronic Pain (longer than 3 months or past the time of normal tissue healing; outside of active cancer treatment, palliative care, and end-of-life care) recommending nonpharmacologic therapy and nonopioid pharmacologic therapy as preferred for chronic pain, and that opioid therapy only be considered if “expected benefits for both pain and function are anticipated to outweigh risks to the patient. If opioids are used, they should be combined with nonpharmacologic therapy and nonopioid pharmacologic therapy, as appropriate (recommendation category: A, evidence type: 3).”6  Access: Gabapentin is inexpensive (referred to among drug‐users as ‘a cheap man's high’) and it is relatively easy to acquire by prescription.9 Prescription gabapentin is the primary source of gabapentin misused in the United States and the United Kingdom.9 However, it has been speculated that gabapentin (if assuming that gabapentin overdoses are less life-threatening than with other drugs) may be replacing more toxic other drugs like benzodiazepines on the prescriptions and black market.14  Dosage: Gabapentin can be abused at any dose, but higher doses may be associated with abuse more than lower doses. (e.g., consider higher than therapeutic recommended dose of >3600 mg). Potential intervention strategies include limiting quantities prescribed and cumulative doses, identification of repeat supply issues (eg refill pattern), or education to help curb abuse and diversion.10,26,84

 Indications: Gabapentin is FDA-approved as adjunctive therapy in the treatment of epilepsy (partial onset seizures, with and without secondary generalization) in patients >3 years old, for the treatment of post-herpetic neuralgia in adults, and restless leg syndrome (extended-release).11 Other uses are off-label; however, several off-label uses of gabapentin have supportive evidence and/or clinical guidelines recommending gabapentin as a treatment option (See off-label use section of the report).12,13  Concomitant gabapentin and opioid use: If gabapentin and opioids are used concurrently (combination use is believed to provide better pain relief in certain circumstances85), does the benefit outweigh the risk and is a consideration for lower doses of each agent assessed? Quintero states that gabapentin can interact synergistically with tramadol for alleviating pain.38  Special populations: Gabapentin may be preferred in elderly patients, those with hepatic disease and those with cancer because of its pharmacokinetics (not hepatically metabolized) and limited drug interaction profile.38,86,87  Widely used mostly for off-label indications: Educating prescribers to use caution when prescribing off-label and to consider referring patients to pain specialists who require gabapentin + opioid if necessary for appropriate pain management.10,84  Misuse or abuse/inappropriate use (potential indicators): Behaviors that could indicate misuse include exaggeration of symptoms, requesting specific drugs or higher doses during appointments, doctor shopping or receiving prescriptions for the same medication from multiple prescribers who are at different practice locations, claiming medications were lost or stolen, filling prescriptions at multiple pharmacies, fabrication of prescriptions, requesting not to bill insurance and instead paying out-of-pocket for medications, or requesting very early refills from the pharmacy (>6 days before supply runs out.9,10,88,89  Patient experience evidence: Views and real-world user experience of patients are important because these are rarely captured in conventional randomized-controlled trials.82 The development of tools to capture the experiences of Utah Medicaid patients and prescribers regarding treatment options, monitoring of progress during treatment, and support services available or that they are unaware of may be useful. Marsden et al found that “patients reported that withdrawal symptoms might not be well understood by prescribers, so improved training and guidance for clinicians are required.”82  Urine drug screening (UDS): A negative drug screen for a prescribed medication may indicate diversion. It has been suggested to add gabapentinoids to standard UDS,10,90 but it has not yet been included. It may be useful in patients at high risk of abuse such as those with substance use disorders given that some patients specifically abuse gabapentinoids because it is not detected on routine UDS.10,88,90,91  High risk populations for abuse: Patients with current or past substance use disorder (particularly opioids). Other populations at increased risk for misuse or abuse of gabapentin include patients with psychiatric comorbidities, patients that are suicidal, patients that are vulnerable to the increased ‘pro-drug’ information on the web like children/adolescents, and inmates.9,10,14,38,49,82  Deprivation: Marsden et al in a national mixed-methods study in England found a strong and increasing association between gabapentinoids, opioids, and antidepressants and deprivation. Deprivation was measured by English Indices of Multiple Deprivation (IMD) which is a weighted combination of 37 indicators of income, employment, education, skills and training, health and disability, crime, barriers to housing and services, and living environment. They also state that the “association with increasing deprivation is reflected in the association between chronic pain and unemployment.”82,92

 Consider consultation with behavioral health service experts/referring patients with complex conditions e.g. current or history of alcohol or drug use disorder, or concurrent severe psychiatric disorder  Long-term use: Marsden et al report that public health guidance in England for prescribers on gabapentinoids focuses on avoiding risks of misuse and dependence, without stipulating any limit on duration of treatment.82,93 In March 2018, an estimated 53% of people in England that had prescriptions for gabapentinoids received it long-term (>12 month). The authors of the mixed- method public health review and database study state that whilst it may be appropriate for those with epilepsy to take it long-term, patients being treated for other conditions may be dependent and need support to discontinue taking gabapentinoids.82 The authors state that it is important to ensure that restrictions do not cause unintended negative consequences (ensuring patients can benefit from treatment where needed).82 Bonnet and Scherbaum (2017) did not find any case reports about gabapentin self-administration for longer than one year.14 The only longitudinal study found and described in their paper, is a prospective study in adults using non-medical prescription opioids in Apalachian Kentucky (n=503; self-report questionnaire of psychoactive substances).94 The authors of the systematic review report that this study found a considerable increase of gabapentin misuse in this population within 5 years.14,94

Utah Medicaid Utilization Data

ALL refers to all Medicaid patients including Fee for Service and Accountable Care Organization (ACO) patients. FFS refers to Fee for Service only patients.

A. Overall total utilization of gabapentin (2016-2019) Please refer to Appendix 5 for additional information.

All* gabapentin claims 2016-2019

250000

200000

150000

100000

50000

0 Patients Claims Patients Claims Patients Claims Patients Claims Patients Claims 2016 2017 2018 2019 Total

*FFS and ACO FFS gabapentin claims 2016-2019 90000 80000 70000 60000 50000 40000 30000 20000 10000 0 Patients Claims Patients Claims Patients Claims Patients Claims Patients Claims 2016 2017 2018 2019 Total

 The number of patients and claims for gabapentin appears to be increasing in the FFS population. This may be related to efforts to reduce opioid use.

B. Most commonly used gabapentin formulations (2016-2019)

Most commonly used formulations by FFS patients

GABAPENTIN GRALISE TAB NEURONTIN CAP POWDER 600MG 300MG GABAPENTIN TAB HORIZANT TAB 800MG 600MG ER GABAPENTIN CAP 100MG

GABAPENTIN TAB 600MG

GABAPENTIN CAP 300MG

GABAPENTIN SOL 250/5ML GABAPENTIN CAP 400MG

Ratio of total claims/patients (FFS)

HORIZANT TAB 600MG ER GRALISE TAB 600MG GABAPENTIN POWDER NEURONTIN CAP 300MG GABAPENTIN TAB 800MG GABAPENTIN TAB 600MG GABAPENTIN SOL 250/5ML GABAPENTIN CAP 400MG GABAPENTIN CAP 300MG GABAPENTIN CAP 100MG

0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0

Whilst the pie chart shows the most commonly used formulations, the ratio demonstrated that the liquid formulation is associated with the mot claims per patient. This may reflect pediatric patients and those in care facilities and the flexibility of oral formulations.

C. Age and gender (2016-2019) for ALL and FFS groups

Age and gender ALL

5,000 4,000 3,000 2,000 F 1,000 M 0 <18 18-24 25-34 35-44 45-54 55-64 >64 F 699 873 3,843 4,107 3,258 2,385 310 M 624 484 1,875 2,329 1,975 1,682 168

Age and gender FFS

2,500 2,000 1,500 1,000 F 500 M 0 <18 18-24 25-34 35-44 45-54 55-64 >64 F 172 324 1,698 2,037 1,800 1,229 240 M 151 233 1,273 1,458 1,282 963 139

% of total % of total Age group FFS (12999) ALL (24612) <18 2.48% 5.38% 18-24 4.28% 5.51% 25-34 22.86% 23.23% 35-44 26.89% 26.15% 45-54 23.71% 21.26% 55-64 16.86% 16.52% 65+ 2.92% 1.94%

 The distribution of gabapentin use by age groups appear similar between ALL and FFS patients.

Age and gender ALL pediatric patients

500 400 300 200 F 100 M 0 0-<3 3-5 6-11 12-17 F 42 51 112 494 M 69 58 156 341

Age and gender FFS pediatric patients

100 80 60 40 F 20 M 0 0-<3 3-5 6-11 12-17 F 18 19 35 100 M 27 20 33 71

% of total % of total ped FFS ped ALL Age group (323) (1323) 0-<3 13.93% 8.39% 3-5 12.07% 8.24% 6-11 21.05% 20.26% 12-17 52.94% 63.11%

 It appears more FFS pediatric patients in the 0-<3 and 3-5 years old groups are receiving gabapentin compared to ALL pediatric patients, and fewer in the 12-17 year old group.

D. Diagnoses (FFS all age groups) How many patients had diagnosis codes submitted for the following? However, it is important to consider that there are several limitations when reviewing data based on diagnosis codes. Percentage of total Number of FFS FFS patients that patients with received gabapentin diagnosis code of (2016-2019) Diagnosis grouping interest submitted (n=12,999) A EPILEPSY/SEIZURES 1,421 10.93% N POSTHERPETIC NEURALGIA 21 0.16% R RESTLESS LEGS SYNDROME 521 4.01% B ALCOHOL MISUSE 1,831 14.09% C DRUG DEPENDENCE 3,752 28.86% D DRUG ABUSE 2,966 22.82% E POISONING (any substance) 734 5.65% G ACCIDENTAL POISONING (subset of poisoning) 631 4.85%

 More than a fifth of patients had a diagnosis code submitted (2016-2019) for drug abuse (this population may be at increased risk for abusing gabapentin).

E. Pediatric patients

 A total of 323 pediatric FFS patients under 3 years of age have received prescriptions for gabapentin although it is only FDA-approved as adjunctive therapy in the treatment of epilepsy in pediatric patients >3 years old.12,13

Number of FFS Percentage of total pediatric patients FFS pediatric with diagnosis code patients that of interest received submitted (2016- gabapentin (2016- Diagnosis 2019) 2019) (n=323) A EPILEPSY 101 31.27% N POSTHERPETIC NEURALGIA 0 0% R RESTLESS LEGS SYNDROME 6 1.9% B ALCOHOL MISUSE 10 3.10% C DRUG DEPENDENCE 19 5.88% D DRUG ABUSE 27 8.36% E POISONING (any substance) 14 4.33% G ACCIDENTAL POISONING (subset of poisoning) 9 2.79%

Additional information on diagnosis codes submitted in these patients have been included in appendix 5 (table 4), with select information summarized below.

 33-67% of the FFS pediatric patients in each age group under 9 years old had a diagnosis code for epilepsy, and 5-60% of those 10-17 years old. This suggests lack of diagnosis code submission or off-label, perhaps inappropriate use of gabapentin.  None of the pediatric patients had a diagnosis for postherpetic neuralgia.  3-15% of the FFS pediatric patients in each age group 15-17 years old had a diagnosis for alcohol misuse (none of the remaining pediatric patients had this diagnosis).  6/19 patients that had a diagnosis submitted for drug dependence were under 3 years old; the majority were 15-17 years old. For the youngest patients this may reflect maternal drug abuse.  Patients with a diagnosis for drug abuse were 11-17 years old; the majority were 14-17 years old (5-29% of patients of this age). Gabapentin misuse/abuse may be likely (if drug abuse is a risk factor for gabapentin abuse/misuse) in these patients.  Patients with a diagnosis for poisoning or accidental poisoning were 9-17 years old.

F. Prescribers of gabapentin (FFS) Note that provider information may not be complete and some prescribers have multiple specialties or credentials.

Prescribers by credentials (FFS)

Psychologist LPN Dentist Oral Surgeons Physician Assistant Nurse Anesthetist Cert Social Worker Physical Therapist Podiatrist Registered Nurse Cert Nurse Midwife QMB-Only Prov Osteopath Nurse Practitioner Physician 0 5000 10000 15000 20000 25000 30000 35000 40000 Number of claims

FFS Credentials FFS Credentials Credentials RXs Credentials RXs Physician 36476 Physician Assistant 5 Nurse Practitioner 14480 Oral Surgeons 4 Osteopath 9423 Dentist 3 QMB-Only Prov 1587 LPN 1 Cert Nurse Midwife 285 Psychologist 1 Registered Nurse 254 Unknown 17628 Podiatrist 162 Physical Therapist 100 Cert Social Worker 30 Nurse Anesthetist 11

Top prescribers by specialty (FFS)

Pediatric Neurology Orthopedic Surgery Pulmonary Diseases Obstetrics-Gynecology Neurology Physical Medicine and R Emergency Medicine Family Practice 0 5000 10000 15000 20000 25000 30000 35000 Number of claims

Note that the prescriber assigned to a prescription may not be the originating provider, but rather the primary care provider who is continuing prescriptions written by other, perhaps specialist, providers.

G. Doses

Number of patients that received this daily dosage at any point during our timeframe (2016-2019) All FFS Maximum single Rx dose Dose* Number of patients Dose* Number of patients >3600 mg 285 >3600 mg 118 >2400-3600 mg 2831 >2400-3600 mg 1576 >1800-2400 mg 3105 >1800-2400 mg 1930 900-1800 mg 11924 900-1800 mg 6379 300-<900 mg 5552 300-<900 mg 2598 <300 mg 915 <300 mg 398

Maximum single Rx dose (excluding solutions)◊ Dose* Number of patients Dose* Number of patients >3600 mg 282 >3600 mg 116 >2400-3600 mg 2825 >2400-3600 mg 1573 >1800-2400 mg 3094 >1800-2400 mg 1921 900-1800 mg 11856 900-1800 mg 6359 300-<900 mg 5358 300-<900 mg 2536 <300 mg 737 <300 mg 332 *Used single prescription to calculate this: (Quantity/day supply) x strength of formulation; this is underestimating the number of patients because it does not capture dosing of patients that received multiple prescriptions overlapping/different strength formulations on separate prescription(s). ◊It was unclear whether the quantity in the claims data is the actual mL amount.

Prescribers of patients with >3600mg/day Specialty ALL Specialty FFS ALL Credentials FFS Credentials Specialty RXs Specialty RXs Credentials RXs Credentials RXs Family Practice 2826 Family Practice 919 Physician 3328 Physician 717 Internal Medicine 851 Internal Medicine 145 Nurse Practitioner 1084 Osteopath 446 Emergency Medicine 199 Emergency Medicine 82 Osteopath 972 Nurse Practitioner 206 Physical Medicine and R 193 Neurology 39 QMB-Only Prov 96 QMB-Only Prov 17 Anesthesiology 151 Physical Medicine and R 17 Registered Nurse 40 Cert Nurse Midwife 9 Psychiatry 126 Child Psychiatry 15 Cert Nurse Midwife 39 Registered Nurse 9 Neurology 114 Pulmonary Diseases 11 Physical Therapist 7 Physical Therapist 7 Obstetrics-Gynecology 48 Psychiatry 10 Cert Social Worker 4 Unknown 288 Infectious Diseases 41 General Practice 6 LPN 2 Pulmonary Diseases 33 Anesthesiology 4 Podiatrist 2 Pediatrics 29 Obstetrics-Gynecology 3 Psychologist 2 Child Psychiatry 20 Orthopedic Surgery 2 Physician Assistant 1 Orthopedic Surgery 15 Infectious Diseases 1 Unknown 1611 General Practice 8 Otorhinolaryngology 1 Hematology 3 Unknown 530 Oncology 3 Gastroenterology 2 General Preventive Medi 1 Otorhinolaryngology 1 Unknown 2845

H. Long-term users (>12 months) (2016-2019)

Continuous use is defined as continuous days’ supply for any gabapentin formulation. 30 days missing data/gap was regarded as ongoing. However, if there were >30 days in which there were no days’ supply, we took this to indicate that continuous use had ended.

 Among ALL patients, 4645 are long-term users (4645/24612 x 100 = 18.9%).  Among FFS patients, 1296 are long-term users (1296/12999 x 100 = 10%).

Prescribers of long-term gabapentin users are shown below.

ALL Credentials FFS Credentials Credentials RXs Credentials RXs Physician 63454 Physician 16449 Nurse Practitioner 23221 Nurse Practitioner 4995 Osteopath 14275 Osteopath 4734 QMB-Only Prov 4849 QMB-Only Prov 600 Podiatrist 346 Registered Nurse 116 Registered Nurse 343 Podiatrist 69 Cert Nurse Midwife 297 Cert Nurse Midwife 60 Physical Therapist 73 Physical Therapist 25 Cert Social Worker 38 Nurse Anesthetist 9 Group Practice 37 Oral Surgeons 2 Psychologist 21 Cert Social Worker 1 Physician Assistant 18 Dentist 1 Dentist 12 LPN 1 Nurse Anesthetist 11 Unknown 6440 LPN 5 Oral Surgeons 3 Optometrist 1 Unknown 29995

Specialty ALL Specialty FFS Specialty RXs Specialty RXs Family Practice 44965 Family Practice 14221 Internal Medicine 15096 Internal Medicine 3878 Pediatrics 4366 Emergency Medicine 1324 Physical Medicine and R 3997 Pediatrics 1136 Psychiatry 3740 Physical Medicine and R 926 Neurology 3204 General Practice 486 Emergency Medicine 3125 Psychiatry 370 Anesthesiology 2207 Obstetrics-Gynecology 368 General Practice 1046 Neurology 344 Child Psychiatry 909 Pulmonary Diseases 244 Obstetrics-Gynecology 825 Anesthesiology 145 Pulmonary Diseases 806 General Preventive Medi 113 General Preventive Medi 553 Pediatric Neurology 80 Rheumatology 405 Child Psychiatry 61 Infectious Diseases 279 Orthopedic Surgery 29 Pediatric Neurology 256 Gastroenterology 26 Orthopedic Surgery 232 Ophthalmology 23 Specialty ALL Specialty FFS Specialty RXs Specialty RXs Oncology 202 Infectious Diseases 22 Hematology 127 Hematology 21 Gastroenterology 101 Oncology 20 Nephrology 99 Nephrology 18 General Surgery 90 Rheumatology 10 Endocrinology 86 Dermatology 7 Cardiology 83 Cardiology 6 Geriatrics 58 Neurological Surgery 5 Neonatology 41 General Surgery 4 Ophthalmology 41 Pathology 4 Pathology 41 Cardiovascular Diseases 3 Cardiovascular Diseases 31 Geriatrics 2 Gynecology 29 Colon and Rectal Surger 1 Diagnostic Radiology 24 Otorhinolaryngology 1 Neurological Surgery 22 Unknown 12277 Dermatology 21 Otorhinolaryngology 21 Radiation Oncology 21 Plastic Surgery 12 Neuroradiology 10 Neuropathology 8 Aerospace Medicine 7 Diabetes 7 Hand Surgery 7 Cardiovascular Surgery 4 Radiology 3 Urology 3 Pediatric Surgery 2 Colon and Rectal Surger 1 Unknown 58226

I. Additional potential problematic use data

Appendix 6 contains information on: (Table number as listed in appendix listed first e.g. T1)

T1+T3. The number of patients Number of patients (ALL+FFS) by number of prescriptions (in last year) with select diagnoses.

T2+T4. Number of patients (ALL+FFS) by number of prescriptions (in last year) that fulfil select criteria (>1 Gabapentin (within 30 days), 1 Pharmacy (within 30 days), >1 Prescriber (GABA/Opioid) within 30 days, >3600mg/day, >400 days’ supply (year), concurrent pregabalin, concurrent opioid, concurrent benzodiazepine, concurrent opioid and benzo, concurrent "muscle relaxant", concurrent hypnotic, concurrent opioid+benzo+muscle relaxant+hypnotic)

 Patients that have more than 25 prescriptions in the 1-year period were reviewed briefly and they fall into 2 categories. Patients that are receiving short days’ supply and patients that are receiving multiple gabapentin prescriptions each refill day. One patient was filling 3 different gabapentin prescriptions of different strengths at each refill date.

T5. Prescribers of patients with >400 days’ supplied from Oct 1, 2018 - Sep 30, 2019

T6. Diagnosis codes submitted for potential inappropriate gabapentin use/prescribing/patients at increased risk for adverse outcomes for ALL patients; FFS is shown below.

Gabapentin fills (FFS) from Oct 1, 2018 - Sep NUMBER OF PATIENTS WITH THESE DX 30, 2019 A N R B C D E G POSTHER- PETIC RESTLESS LEG ALCOHOL DRUG ACCIDENTAL Any dx EPILEPSY NEURALGIA SYNDROME MISUSE DEPENDENCE DRUG ABUSE POISONING POISONING >1 Prescriber (GABA/Opioid) within 30 days 836 243 7 105 258 540 395 104 94

>1 Pharmacy (within 30 days 706 162 2 60 237 565 461 99 94

Patients with >3600mg/day* 26 12 1 2 6 21 17 6 4 Patients with >400 days’ supply (year)♦ 71 21 0 7 16 51 40 11 6 PATIENTS WITH Concurrent opioid (within 30 days) 1119 317 8 141 329 706 503 133 128 PATIENTS WITH Concurrent PREGABALIN (within 30 days) 156 36 0 15 43 125 94 23 20 PATIENTS WITH Concurrent benzodiazepine (within 30 days 1007 337 3 78 323 660 493 143 141 Patient with concurrent opioid and benzo (within 30 day 387 157 2 39 99 242 164 49 57 Patient with concurrent muscle relaxant (within 30 days) 910 239 10 111 267 585 416 96 92 Patient with concurrent hypnotic within 30 days) 210 56 1 28 55 143 112 34 32 Patient with concurrent opioid+benzo+ muscle relaxant+ hypnotic (within 30 days) 25 11 0 3 7 16 12 3 3 *Used single prescription to calculate this: (Quantity/day supply) x strength of formulation; this would not capture dosing of patients that received multiple prescriptions overlapping/different strength formulations on separate prescription. ♦This would be an overestimate if patients received multiple prescriptions overlapping/different strength formulations on separate prescriptions.

Conclusions

Abuse liability of gabapentin in the general population (1.1%) appears low compared to abuse prevalence rates involving other drugs.10,95 Current or past substance abusers (particularly opioids), patients with psychiatric comorbidities, patients that are suicidal, patients that are vulnerable to the increased ‘pro-drug’ information on the web like children/adolescents, and inmates, may be at increased risk for abusing gabapentin. Prescribed gabapentin appear to be a major source of the abused/misused gabapentin. Some fatal overdoses have been reported where gabapentin was assumed to be the main cause of death. Concurrent use with opioids and other CNS depressants increases the risk for adverse outcomes. Doses needed for abuse-related effects include therapeutic doses, and supratherapeutic doses.9,10,14,38,49,82

Gabapentin is an important treatment option for many patients. This includes use in combination with opioids because it offers augmentation of opioid therapy although risk of adverse events increases and the risk/benefit ratio must be considered in any individual patient. It is important to ensure access where use may be warranted especially to help reduce the use of opioids. However, the risks of abuse/misuse and toxicity should be considered especially in populations at risk. Evidence on gabapentin’s risk of misuse and abuse continue to emerge, requiring review of its use to identify any potential signs and risk factors for abuse.

Review of the Utah Medicaid Utilization data indicated that patients receiving gabapentin include patients that may be at increased risk for abusing gabapentin. Also, patients are receiving concurrent CNS drugs which may increase the risk of central nervous system and respiratory depression.

Appendix 1 – Drug information

Table 1. Summary of Gabapentin Dosing Recommendations

Source Indication Dosing Neurontin (Gabapentin) Package Insert, FDA Postherpetic  Dose can be titrated up as needed to a 201711 Neuralgia dose of 1800 mg/day; efficacy was demonstrated with doses from 1800 mg/day to 3600 mg/day with comparable effects across the dose range Epilepsy with  ≥ 12 years old: 900 to 1800 mg/day (in Partial Onset 3 divided doses) Seizures  See labeling for weight-based dosing for younger age groups Horizant (gabapentin enacarbil) Package Restless Legs  600 mg once daily taken at about 5 Insert, 2012 Syndrome PM

Postherpetic  600 mg in the morning for 3 days, neuralgia in then increase to 600 mg twice daily adults beginning on day 4 VA/DoD Clinical Practice Guideline for the Alcohol Use  Increase by 300mg daily as tolerated Management of Substance Use Disorders, Disorder to target of 1800mg daily (in 3 divided Department of Veterans Affairs and doses) Department of Defense (2015)96 Treatment of Unexplained Chronic Cough: Chronic  300 mg/day to 900 mg twice a day CHEST Guideline and Expert Panel Report Refractory (Gibson et al., 2016)65 Cough Diabetic Neuropathy: A Position Statement Diabetic  IR formulation: 900 to 3600 mg/day in by the American Diabetes Association (Pop- Neuropathy two or three divided doses Busui et al., 2017)71

Evidence-based guideline: Treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation (2011)70

Source Indication Dosing Pharmacotherapy for neuropathic pain in Neuropathic  IR formulation: 1200 to 3600 mg/day adults: systematic review, meta-analysis and Pain in two or three divided doses updated NeuPSIG recommendations  ER formulation: 300 to 600 mg/day in (Finnerup et al., 2015)66 two divided doses

 Populations studied were those with postherpetic neuralgia, diabetic and non-diabetic painful polyneuropathy, postamputation pain, post- traumatic/postsurgical neuropathic pain including plexus avulsion and complex regional pain syndrome type II, central post-stroke pain, spinal cord injury pain, multiple sclerosis- associated pain and neuropathic pain associated with nociceptive components (eg, cancer neuropathic pain and radiculopathy)  Excluded conditions such as complex regional pain syndrome type I, low back pain without radicular pain, fibromyalgia, and atypical facial pain Management of Postoperative Pain: A Postoperative  IR formulation: 300-1200mg as a Clinical Practice Guideline From the Pain single dose, given 1-2 prior to surgery American Pain Society, the American Society or immediately after surgery; higher of Regional Anesthesia and Pain Medicine, doses might be more effective but can and the American Society of increase risk of sedation Anesthesiologists' Committee on Regional Anesthesia, Executive Committee, and Administrative Council (Chou et al., 2016)72 Guidelines for the first-line treatment of Restless Leg  IR formulation: 900 -2400 mg/day restless legs syndrome/Willis-Ekbom disease, Syndrome  ER formulation: 600-1200 mg/day prevention and treatment of dopaminergic augmentation: a combined task force of the IRLSSG, EURLSSG, and the RLS-foundation (Garcia-Borreguero et al., 2016)80

Appendix 2 – Search strategy Searches performed on 11/04/2019.

Pubmed Items Notes Search Query found

#7 Search #6 NOT ("Animals"[Mesh] NOT "Humans"[Mesh]) 1 Utah studies

#6 Search #1 AND #5 1

#5 Search Utah 63671

#1 Search gabapentin AND (abuse OR misuse OR non-medical OR nonmedical OR illicit OR addict OR 1306 addiction OR diversion OR dependence OR drug-seeker OR drug-seeking OR trafficking OR inappropriate OR overprescribing OR overprescribed OR overprescribers OR overtreating OR overdiagnosis OR high)

#4 Search #2 OR #3 141 Systematic Reviews

#3 Search #1 and systematic[filter] 90

#2 Search #1 AND ((((((((((("Meta-Analysis as Topic"[Mesh]) OR meta analy*[tw]) OR 125 metaanaly*[tw]) OR Meta-Analysis[pt]) OR (((systematic AND (review* OR overview*)) AND tw))) OR "Review Literature as Topic"[Mesh])) OR ((((((((cochrane[tiab]) OR embase[tiab]) OR ((psychlit OR psyclit[tiab]))) OR ((psychinfo OR psycinfo[tiab]))) OR ((cinahl OR cinhal[tiab]))) OR science citation index[tiab]) OR bids[tiab]) OR cancerlit[tiab])) OR (((((reference list*[tiab]) OR bibliograph*[tiab]) OR hand-search*[tiab]) OR relevant journals[tiab]) OR manual search*[tiab])) OR ((((selection criteria[tiab]) OR data extraction[tiab])) AND "Review"[pt]))) NOT (((("Comment"[pt]) OR "Letter"[pt]) OR "Editorial"[pt]) OR (("Animals"[Mesh]) NOT (("Animals"[Mesh] AND "Humans"[Mesh]))))

Query translation (#1; 1306 results) ("gabapentin"[MeSH Terms] OR "gabapentin"[All Fields]) AND (("substance-related disorders"[MeSH Terms] OR ("substance- related"[All Fields] AND "disorders"[All Fields]) OR "substance-related disorders"[All Fields] OR "abuse"[All Fields]) OR misuse[All Fields] OR non-medical[All Fields] OR nonmedical[All Fields] OR illicit[All Fields] OR addict[All Fields] OR ("behavior, addictive"[MeSH Terms] OR ("behavior"[All Fields] AND "addictive"[All Fields]) OR "addictive behavior"[All Fields] OR "addiction"[All Fields]) OR diversion[All Fields] OR ("dependency (psychology)"[MeSH Terms] OR ("dependency"[All Fields] AND "(psychology)"[All Fields]) OR "dependency (psychology)"[All Fields] OR "dependence"[All Fields]) OR drug-seeker[All Fields] OR ("drug-seeking behavior"[MeSH Terms] OR ("drug-seeking"[All Fields] AND "behavior"[All Fields]) OR "drug-seeking behavior"[All Fields] OR ("drug"[All Fields] AND "seeking"[All Fields]) OR "drug seeking"[All Fields]) OR trafficking[All Fields] OR inappropriate[All Fields] OR overprescribing[All Fields] OR overprescribed[All Fields] OR overprescribers[All Fields] OR overtreating[All Fields] OR ("medical overuse"[MeSH Terms] OR ("medical"[All Fields] AND "overuse"[All Fields]) OR "medical overuse"[All Fields] OR "overdiagnosis"[All Fields]) OR high[All Fields])

Translations:

gabapentin "gabapentin"[MeSH Terms] OR "gabapentin"[All Fields] "substance-related disorders"[MeSH Terms] OR ("substance-related"[All Fields] AND abuse "disorders"[All Fields]) OR "substance-related disorders"[All Fields] OR "abuse"[All Fields] "behavior, addictive"[MeSH Terms] OR ("behavior"[All Fields] AND "addictive"[All addiction Fields]) OR "addictive behavior"[All Fields] OR "addiction"[All Fields] "dependency (psychology)"[MeSH Terms] OR ("dependency"[All Fields] AND dependence "(psychology)"[All Fields]) OR "dependency (psychology)"[All Fields] OR "dependence"[All Fields]

"drug-seeking behavior"[MeSH Terms] OR ("drug-seeking"[All Fields] AND drug-seeking "behavior"[All Fields]) OR "drug-seeking behavior"[All Fields] OR ("drug"[All Fields] AND "seeking"[All Fields]) OR "drug seeking"[All Fields] "medical overuse"[MeSH Terms] OR ("medical"[All Fields] AND "overuse"[All Fields]) OR overdiagnosis "medical overuse"[All Fields] OR "overdiagnosis"[All Fields]

Epistemonikos (title:(gabapentin) OR abstract:(gabapentin)) AND (title:(abus* OR misus* OR non-medical OR nonmedical OR illicit OR addict* OR diversion OR depend* OR drug-seek* OR trafficking OR inappropriate OR overprescrib* OR overtreat* OR overdiagnos* OR high) OR abstract:(abus* OR misus* OR non-medical OR nonmedical OR illicit OR addict* OR diversion OR depend* OR drug- seek* OR trafficking OR inappropriate OR overprescrib* OR overtreat* OR overdiagnos* OR high)) Limited to systematic reviews (105 results)

Figure 1 – PRISMA flowchart Figure 1. Flow diagram for systematic reviews included

Records identified through database Duplicates removed searching and other sources (n = 74) (n = 244)

Records after duplicates removed (n = 170)

Records screened Records excluded (n = 170) (n = 160)

Full-text articles assessed Full-text articles excluded, with for eligibility reason (n = 10) (n = 4*)  Not about gabapentin abuse or misuse  General review  Appears to be a descriptive Systematic reviews report/duplicate of the original included in qualitative systematic review in another synthesis language (abstract available in (n = 6) English); no response from author

*List of excluded studies 1. Vickers Smith R, Boland EM, Young AM, et al. A qualitative analysis of gabapentin misuse and diversion among people who use drugs in Appalachian Kentucky. Psychology of Addictive Behaviors. 2018;32(1):115-121. 2. Reinert JP, Dunn RL. Management of overdoses of loperamide, gabapentin, and modafinil: a literature review. Expert Review of Clinical Pharmacology. 2019;12(9):901-908. 3. Bonnet U, Scherbaum N. [On the risk of dependence on gabapentinoids]. Fortschritte der Neurologie-Psychiatrie. 2018;86(2):82-105. 4. Rudisill TM. Drug use and the risk of motor vehicle collision in adults 65 years of age and older. Dissertation Abstracts International: Section B: The Sciences and Engineering. 2016;76(12-B(E)).

Appendix 3 – Systematic review evidence

Table 1. The Problem: Gabapentin abuse data from systematic reviews Reference Sources of Drug effect sought by Toxic effects/Clinical Prevalence of gabapentin misuse Overdoses/outcomes related to abused/misused abusers/reasons for abuse presentation or abuse gabapentin abuse/misuse gabapentin or misuse DEA July Annual total To “get high” FDA-labelled information 15% of 503 adults reporting AAPCC 20198 prescriptions for nonmedical use of Involved in 168 fatalities in 2012- gabapentin increased Sedative and psychedelic pharmaceuticals 2016; gabapentin was primary over two-fold from effects (based on study that cause in 23 individuals. 2,965,784 in 2011 to analyzed information from 1.1% self-reported lifetime Total gabapentin exposure calls: 6,722,145 in 2017 (IMS 32 websites) prevalence of gabapentin misuse 72,283 (2012-2016); 5,889 (2012) Health™). (2013 online survey; 1500 and 20,064 (2016) respondents from UK; 16-59 years Single substance exposure Commonly offered for old) (gabapentin alone): increased sale from numerous from 2,141 (2012) to 7,024 websites. Rates of diversion steadily (2016). increased from 0.0 in 2002 to 0.027 cases per 100,000 DAWN population in 2015. ED visit rates (per 100,000 population) for gabapentin: 2016 Reports for gabapentin (6.5- increase from 2.7 (2004) to 4.9 6.75-fold increase from 2007) (2011) STARLiMS (web-based, commercial laboratory information management system) and STRIDE (System to Retrieve Information from Drug Evidence): 28 reports Federal databases for seized drugs analyzed by DEA forensic laboratories, and NFLIS (the National Forensic Laboratory Information System that collects drug analysis information from state, local, and other federal forensic laboratories): 2,219 reports.

Reference Sources of Drug effect sought by Toxic effects/Clinical Prevalence of gabapentin misuse Overdoses/outcomes related to abused/misused abusers/reasons for abuse presentation or abuse gabapentin abuse/misuse gabapentin or misuse RADARS system (Researched Abuse, Diversion and Addiction Related Surveillance System; prescription drug abuse/misuse and diversion monitoring system that collects geographically- specific data): 407 cases of gabapentin diversion were reported in 41 states between 2002 and 2015.

Quintero 52% physicians, Motivation for getting Route of administration 1.1-19% 43 cases of gabapentin 201738 36% drug dealers “high” impact side effects. (postmortem toxicology analysis; (US$1/pill)(Appalachian To alleviate opioid Teratogenicity, 1.1% lifetime misuse (online UK 2010,2011 Finnish study); 18.6% Kentucky)94 withdrawal symptoms hypoventilation, respiratory survey; 1500 participants)95 of gabapentin findings associated To potentiate methadone failure, deficits in visual with drug abuse; Increase in number of high field, myopathy, self-harm 4.8% misuse/abuse or Gabapentin poisoning accounted patients asking for behavior, suicidal behavior, dependence (EudraVigilance for 4.7% of all gabapentin-related gabapentin (Scotland)90 mitochondrial toxicity, database; 2004-2015)41 deaths. somnolence, dizziness and For those with drug abuse asthenia. 15% misuse of 503 participants problems, 12.5% showed last 6 months (for getting high); gabapentin poisoning. used 25 of 30 previous days In the gabapentin abuser group, (Appalachian study in Kentucky)94 87.5% of cases showed concomitant opioid use.40 16% lifetime misuse (250 former inmates); 26% of patients with 86 gabapentin fatalities opioid disorder and 4% of (EudraVigilance database; 2004- patients without opioid use 2015)41 disorder.97

19% (25/129) use without prescription (Scotland survey)98 Schifano Increasing Psychoactive effects Increasingly being reported to be Increase in overdoses involving 201826 prescriptions and include a sense of well- abused in the EU10,27; no specific gabapentinoids (Emergency growing black being/relaxation, euphoria, levels Department presentations market10,27 and hallucinations.100 involving intentional drug overdoses recorded by the National Self-Harm

Reference Sources of Drug effect sought by Toxic effects/Clinical Prevalence of gabapentin misuse Overdoses/outcomes related to abused/misused abusers/reasons for abuse presentation or abuse gabapentin abuse/misuse gabapentin or misuse (Shutting ‘rogue’ (“Within both online drug Registry (Ireland; 2007–2015) pharmacies typically forum communities and Gabapentinoid fatalities are prompts sellers to social typically observed in combination move to servers in networks, there are some with other psychoactive drugs overseas countries, educated/informed users (especially leading to a growing (the ‘psychonauts’)29 who opioids and other sedatives)91,102 black market)99 typically ‘test’ a range of psychotropics, including prescribed drugs, to achieve specific mindsets and eventually, share this information with peers.”)26,101 Evoy 2017 Prescription and non- To achieve euphoric highs May differ based on 1.6% gabapentinoid abuse in High doses are generally not prescription (street (those abusing opioids that tolerance and dose; general population; UK; 16-59 lethal, but gabapentinoids are value $1-7 or may be have developed tolerance supratherapeutic doses: years old (1.1% gabapentin and increasingly identified in post- traded for other may desire effects of new sedation, dissociation, 0.5% pregabalin)95 mortem toxicology analyses. drugs)88,90,94,98 drugs) relaxation, contentment, numbness, uninhibited 3-68% abuse among opioid 116 cases of gabapentin Most often obtained To become intoxicated or behavior, improved abusers (15-22% gabapentin and overdose; 23 for pregabalin; no from healthcare potentiate the effect of sociability, empathy, audio 3-68% pregabalin) deaths; mild-moderate severity providers (63.1%), methadone, or and visual hallucinations outcomes; estimated median family or buprenorphine/naloxone, (anecdotal descriptions of 11,940 reports of gabapentinoid gabapentin dose 6000 mg (96000 acquaintances and to avoid detection users) abuse (4301 gabapentin and 7639 mg max) (2002-2011 American (57.8%), internet during routine urine drug pregabalin) 2004-2015 (>75% poison center database)104 purchase (47.3%), and screening (UDS reported since 2012) abroad (7.8%)95 monitoring)88,91,97,98 (international adverse event 86/410 (21%) fatalities in patients database).41 abusing gabapentin (83 cases 40% of opioid Less common: to self- involved co-ingestants) (2004- dependent patients medicate uncontrolled 18.6% of gabapentin cases of mid-2015 International AE prescribed gabapentin pain, anxiety or withdrawal Finnish autopsy cases involving reporting system, Eudra- admitted to misusing it of other drugs/minimize gabapentinoids deemed drug Vigilance); third of cases in (vs.13% without a cravings (e.g., cocaine, abuse.40 2014).41 prescription).103 opioids or alcohol) 36/48 post-mortem exams 22% of 29 patients in a (Scotland) that included Scottish methadone gabapentin also included clinic used non- methadone and/or morphine.90 prescribed

Reference Sources of Drug effect sought by Toxic effects/Clinical Prevalence of gabapentin misuse Overdoses/outcomes related to abused/misused abusers/reasons for abuse presentation or abuse gabapentin abuse/misuse gabapentin or misuse gabapentinoids (19% Gabapentinoids found in 2.61% of gabapentin).98 13,766 autopsies (Finland); 43 (0.31%) gabapentin identified cases.40 Marsden This mixed-method Report in introduction that NR Long-term prescribing is common Little evidence was found for 201982 public health review early reports for withdrawal for gabapentinoids; focuses on the gabapentinoids included no specific information for dependence or euphoria, sedation and gabapentin. withdrawal of dissociation and thought to prescribed medicines have a low risk of (including gabapentin) dependence and Prescriptions for withdrawal.9,10 but recent gabapentinoids evidence shows the risks increased from 2.7 when taken with opioids million in 2008 to 14.4 (dangerous respiratory million in 2018. depression).105 Smith Major source is health Primarily for recreational Various including CNS 1.1% in general population (UK);95 Scotland (2010): Approximately 20169 services/physicians purposes, self-medication symptoms, GI symptoms, 40–65% among individuals with 1% of all drug-related deaths (52-63% in UK and or intentional harm cardiac symptoms, prescriptions94,95,103,106 and were attributed directly to US)94,95(prescriptions, (suicide) neuromuscular between 15 and 22% within gabapentin.98 own medication), To potentiate the effects of symptoms, seizures, populations of people who abuse 0.6% of 23, 479 impaired driving family, friend, methadone.98 nystagmus, coma, opioids.94,98,103 cases in the United States internet/online Used as a cutting agent for respiratory depression involved gabapentin (Washington pharmacies, abroad, heroin.90 state 2003-2007).111 drug dealers (street Substitute for cocaine.88,110 Gabapentin in 0.3% of 13 766 market 1 GBP per 300 medico-legal postmortem case mg, 1-7 US$ per pill Several subjective investigations (Finland).40 depending on strength) experiences reminiscent of 39,49,94,95,98,106-109 opioids, benzodiazepines and psychedelics were reported (to be interpreted with caution): Feeling ‘high’ (cocaine-like ‘high’) or ‘stoned’ ‘amphetamine rush’, ‘fully sedated opiate buzz’, ‘disassociation like DXM’, ‘talkative’, ‘comparable to cannabis’,

Reference Sources of Drug effect sought by Toxic effects/Clinical Prevalence of gabapentin misuse Overdoses/outcomes related to abused/misused abusers/reasons for abuse presentation or abuse gabapentin abuse/misuse gabapentin or misuse ‘buzz slightly reminiscent of MDMA’, euphoria, improved sociability, a marijuana-like ‘high’, relaxation, sense of calm, ‘zombie-like’ effects, increased energy and focus, and improved sleep. Bonnet Prescriptions (good To get high, to potentiate Refer to overdose cases Rough estimation for general Recommended maximum and portion off-label use), an opioid high or to population therapeutic blood level is 30 Scherbaum internet, black markets dampen withdrawal Life-prevalence of dependence: mg/L.113 201714 symptoms or anxiety. 0.25% (elderly German hospital Nonfatal overdoses population)112 9 case presentations (table 3) and Authors state robust Life-prevalence of misuse: 0.5– one case series mostly in evidence that opioid users 1.1%, (younger British internet- combination with other drugs.106 (including multiple drug population).95 Highest described blood levels users) selected were nearly 4-fold the gabapentinoids mainly to 15-22% for opioid recommended maximum boost a euphoric high and dependent/using (self- therapeutic blood level (2 cases: reduce withdrawal administering) patients and those coma, respiratory depression or symptoms while producing in opioid substitution programs cardiopulmonary resuscitation only few adverse (up-to-6-month rates)94,97,98 but also related to overdosing effects.49,94,97,98,103 with concurrent medications).114,115 Two case reports for gabapentin alone with lower blood levels: 62mg/L39 and 72.8mg/L116 with sedation and nausea but stable vital signs. One case117 of a 30-year-old woman with epilepsy and renal insufficiency with blood concentrations of nearly 3-times the maximum level) after a dose increase to 1800 mg daily together with valproate: developed mild resting tremor and cognitive deficits

Reference Sources of Drug effect sought by Toxic effects/Clinical Prevalence of gabapentin misuse Overdoses/outcomes related to abused/misused abusers/reasons for abuse presentation or abuse gabapentin abuse/misuse gabapentin or misuse Overdoses together with other substances were more toxic; parenteral applications of gabapentin is described by others.49

Fatal overdoses: 6 postmortem case reports with gabapentin assumed to be the main cause of death.41,108,118,119 2 of these cases involved excessive and pure gabapentin (alone) self- poisoning.108,119

American Association of Poison Control Centers (2012–2015)120- 123: total fatality rates have been falling, but gabapentinoid-related fatalities had increased from 1.5% (n=38; 31 is gabapentin) to 4.3% (n=59; 51 is gabapentin)

Table 2. Targets for interventions: Gabapentin abuse data from systematic reviews Reference Populations at increased risk for misuse or abuse Doses needed for abuse-related effects Factors increasing the abuse effect/risk for overdose or death

DEA July Based on 2 studies reported in prevalence section, it NR NR, but they state: 2019 appears possibly higher in “nonmedical users of Gabapentin is not currently a Controlled Substance. pharmaceuticals” Increase in number of prescriptions (>double from 2011 to 2017) Commonly offered for sale online

Reference Populations at increased risk for misuse or abuse Doses needed for abuse-related effects Factors increasing the abuse effect/risk for overdose or death

Quintero 5.2% of patients attending misuse services for at least Average dose of patients (described in Majority of fatalities consisted of a combination of 201738 4 years had prescription for gabapentin and these population column; Scotland study) was gabapentin and opioids (EudraVigilance database; subjects were at least 3 times more likely to accept 1343 mg.90 2004-2015)41 misuse of analgesics (P=0.0006; Scotland study)90

Misuse/abuse or dependence mainly women (EudraVigilance database; 2004-2015)41

Patients with opioid disorder (26% vs. 4% without opioid use disorder).97 Schifano Patients that are suicidal (Intentional drug overdoses 1000-4800 mg alone or in combination with High dosages and polydrug abuse (especially 201826 recorded by the National Self-Harm Registry (Ireland; other drugs based on reports from “web opioids and other sedatives whose effects are 2007–2015), showed that gabapentinoids have been enthusiasts”26,125 potentiated by gabapentinoids)91,102,124 increasingly identified over time)124 Potential strategy: Identify a repeat supply Patients that are vulnerable to the increased ‘pro-drug’ issue (authors of systematic review)26 information on the web (with increased access to the web) like children/adolescents and psychiatric patients101

Inmates or people with a misuse or abuse history (systematic review authors’ conclusion)26

Evoy Current or past substance abusers (particularly opioids, Typically involves supratherapeutic doses Deaths more common when coingested with other 201710 but also past cocaine use,39,88,110,126 concurrent use (often in clear excess of the max CNS depressants. Most gabapentinoid-related with cannabis,98 benzodiazepine,94,98 and as a cutting recommended dose of 3600 mg/day) fatalities involve opioids.41 agent for heroin90) and psychiatric comorbidities (risk Opioids found in 87.5% of gabapentin abuse cases of factor for most drugs of abuse, but increase 600 and 1200 mg produced similar drug- Finnish autopsy cases involving gabapentinoids.40 prevalence in gabapentin abuse may be due to off- liking to oral tetrahydrocannabinol (THC; (there were 43 gabapentin identified cases and label use for psychiatric conditions).90,97,98,103 active of cannabis) and increased THC drug- 18.6% were attributed to drug abuse) liking when administered concurrently (8 Former inmates with both psychiatric and SUD cannabis users)127 Mostly taken orally, but other routes have been diagnoses (41/250=16% of those surveyed misused reported including injecting, smoking, or inhaling gabapentin); 26% (37/145) of those with opioid use Median dose of 9 case reports/series (14 crushed tablets, rectal plugging, or parachuting disorder vs.4% (4/105) without.97 patients) of gabapentin abuse was 3600 mg (emptying crushed tablets or capsule contents into a (range of 1500-12,000 mg)88,89,91,109,110,126,128- pouch (e.g., toilet paper) and swallowing, in order to 130 absorb larger quantities at one time while avoiding

Reference Populations at increased risk for misuse or abuse Doses needed for abuse-related effects Factors increasing the abuse effect/risk for overdose or death

Widespread diversion and highly sought after drug in When abused doses are typically not taken the taste of the drug.126,131 (some information may prisons (US and Scotland)98,126 as 3-4 divided doses/day, but as a single apply to pregabalin) supratherapeutic dose. Scotland study shows patients in substance misuse Concurrent abuse of other drugs services prescribed gabapentin were >3 times more Due to quick development of tachyphylaxis, likely to admit to non-medical use of analgesics.90 repeat users may continue to increase the dose. Typical gabapentin abusers are young (30 vs 58 years old in a Finnish study).40 Frequency of gabapentinoid abuse Conflicting data regarding gender abuse differences, General population (survey): 13.1% >once but cite pregabalin and gabapentin studies (the weekly; 50% once weekly–once monthly; authors mention the Eudravigilance data indicating 36.8% less frequently.95 more females, but substantially more women were Opioid abusers use an average of 25 of the included in the total number of adverse drug past 30 days (survey).94 reactions;41 also, a study in opioid abusers in which 77.8% of patients that tested positive for gabapentin were female94)

Marsden Refer to factors (mental health diagnosis and OUD) NR They mention evidence of dangerous respiratory 201982 depression when gabapentinoids are taken with opioids (introduction)37 They reported on studies identified for factors that contribute to the risk of harms associated with dependence and the short term discontinuation or longer term withdrawal symptoms from opioids for chronic pain (excluding end of life /palliative care/cancer pain), benzodiazepines, Z-drugs, gabapentin and pregabalin (excluding epilepsy treatment), and antidepressants.

No specific findings were reported for gabapentin.

Smith Authors of review: Individuals with histories of drug A range of doses, including those within Most commonly found substances with gabapentin 20169 abuse. clinical recommendations (900-3600 mg) and include alcohol49 and/or opioids (2010-2011 Finnish supratherapeutic doses. postmortem toxicological samples),40 morphine and Based on information found in review (interpretation): methadone (75% of gabapentin postmortem Individuals with a history of alcohol abuse or For euphoria reminiscent of, but not as toxicology reports cases in Scotland),90 and dependence do not appear to be at increased risk.103 strong as opioids (gabapentin used alone or polysubstances in driving impairment cases

Reference Populations at increased risk for misuse or abuse Doses needed for abuse-related effects Factors increasing the abuse effect/risk for overdose or death

in combination with other drugs e.g. (benzodiazepines (44%), opioids (43%), Possibly inmates: Only 19/96 prescriptions amongst buprenorphine/naloxone, methadone, antidepressants (43%), other central nervous system inmates were in the possession of the person that baclofen, quetiapine, alcohol) actual abused (CNS) depressants (e.g. trazodone, zolpidem; 36%), received the prescription.126 dosage ranges were provided by 3 papers anti-epileptics (25%), cannabinoids (15%), stimulants ranging from 1500 to 12000 mg.88,91,130 (11%) and ethanol (6%)( Washington State in 2003- 2007),111 and cannabis, For sedation/relaxation/calmness (alone or selective serotonin reuptake inhibitors (SSRIs), in combination with other drugs e.g. lysergic acid quetiapine, alcohol, cannabis, diethylamide (LSD), amphetamine and GHB buprenorphine/naloxone) a range of 600- (gammahydroxybutyric acid) (review).49 4800 mg was reported. Those misusing gabapentin may also be misusing Based on some studies, those with buprenorphine.94 prescriptions use more than prescribed (potentially due to tolerance and Substance abuse populations: greater likelihood for addiction),40,89,103,129 and those without those misusing gabapentin to also be misusing prescription often took doses within clinical prescription opioids and benzodiazepines.90 recommendation limits, but doses were not spread out during the day and frequency of dosing was unclear.88 Bonnet Opioid using (self-administering) patients and those in Overdoses together with other substances and opioid substitution programs Scherbaum Gabapentin not regulated by law. 201714 “In comparison with propofol and benzodiazepines, gabapentinoids are certainly the safest GABAmimetics with a higher therapeutic index and wider dose margin between pleasure (euphoria/relaxation) and coma or death by overdosing.“10,14,37,38

Table 3. Implications of lack of or failed interventions (to prevent abuse and adverse consequences): Gabapentin abuse data from systematic reviews Reference Management of intoxication Cost associated with overdose e.g., hospitalizations

DEA July NR NR 20198 Quintero NR NR 201738

Schifano NR NR 201826 Evoy Appears relatively safe even following acute No patients requiring hospitalization in a US Poison center study of 20 201710 overdose; common symptoms include gabapentin exposure.106 hypotension, tachycardia, CNS effects (more severe than with therapeutic doses); Rare reports of fatalities or intensive care unit admissions (ICU); outcomes are generally mild- moderate even with high doses (as high as 96,000 mg); symptoms typically resolved within 10 hours in case series; reports of patients surviving 91000 mg (25 times max dose) even with coingestion of other substances; severe cases may be more common with renal impairment.39,40,104,106,108,114-117,119,132-134 Marsden They reviewed several aspects of dependence NR 201982 or withdrawal, including management, prevention and treatment approaches, patient experiences, and support services (including opioids, benzodiazepines, antidepressants, Z- drugs, and gabapentinoids), but did not report any specific information for gabapentin about these aspects in the manuscript.

Smith NR NR 20169

Bonnet NR NR and Scherbaum 201714

Appendix 4 – Utah Poison Control Center: Gabapentin exposures

Utah Poison Control Center

Gabapentin exposures

January 1, 2014 – September 30, 2019

The Utah Poison Control Center (UPCC) was consulted on the management of 2,011 cases involving gabapentin between January 1, 2014 and September 30, 2019.

Year Gabapentin Total UPCC Gabapentin Intentional total % Human exposures (% Exposures intentional intentional Exposures of total) exposures exposures 2014 260 41,012 0.6 153 4817 3.2 2015 306 41,210 0.7 179 5048 3.5 2016 278 41,509 0.7 177 5438 3.3 2017 417 39,474 1.1 260 5809 4.5 2018 411 39,730 1.0 264 6113 4.3 2019* 339 31,038 1.1 218 4879 4.5 Total 2,011 233,973 0.9 1,251 32,104 3.9

I. Gabapentin

A. Reason for exposure

The reason for exposure is documented by the specialist in poison information and is based on the history, circumstances and other evidence during the course of the poison center involvement with the case - which is typically until the situation has resolved (home cases) or the patient is medically cleared. It is sometimes difficult to discern true intent – specifically discerning between intentional misuse, abuse or intentional suicide. The poison center utilizes psychiatry consultation notes whenever possible to try to accurately define the reason when the situation is unclear. . Unintentional (664; 33%) o Unintentional general (exploratory behavior/dementia): 211(10.5%) o Therapeutic error: 446 (22.2%) . Intentional (1,251; 62.2%) o Suspected suicide: 1,013 (50.4%) o Misuse: 112 (5.6%) o Abuse: 71 (3.5%) . Other (22; 1.1%) . Adverse reaction (59; 2.9%) . Unknown (15; 0.8%)

Reason by Age . All but one case involving children <= 5 years was coded as unintentional. o 95% unintentional general (oral exploration) o 4.5% therapeutic error o 1 case was coded as Other – specifically concern for withdrawal (likely a newborn) . 6-12 years of age o 66.7% unintentional with the majority coded as therapeutic error o 6 (28.6%) were coded as intentional – with suicide attempt the reason in 2/3 . 13-19 years of age o 136 (84%) of cases in this age group were for intentional reason – with the majority suicide attempt. . Adults o The majority (68%) were coded as intentional with suicide the most common intentional code. Abuse was coded in only 3.5% of adult cases.

B. Age and Gender . 202 (9.95%) <= 5 years of age . 1623 (80.71%) >= 20 years of age . 1,193 (59.32%) female . ~ 60% of all exposures reported to UPCC involve children <= 5 years of age.

C. Caller, Exposure and Management Site . 1,807 (89.8%) of exposures occurred at a residence . 1,105 (54.9%) consults originated from a health care facility . 525 (26.1%) of exposures were managed onsite . 1,374 (68.3%) of exposures were managed in a healthcare facility o 479 (22.8%) treated and released from emergency department o 314 (15.6%) admitted for critical care unit o 211 (10.5%) admitted to noncritical care unit o 312 (15.5%) admitted to psychiatric facility

D. Medical Outcome . 447 (22.2%): no effect . 799 (39.7%): minor effect . 413 (20.5%): moderate effect

. 91 (4.5%): major effect . 3 (0.2%): death . 177 (8.8%): not or unable to follow . 81 (4%): effects unrelated to exposure

E. Additional Substances

The Utah Poison Control Center captures all potential substances involved in a poisoning exposure. More than one substance is involved in the majority of self-harm attempts. The following substances were also involved in cases involving gabapentin. The numbers reflect the number of times the substance was documented on a record and not the number of patients. The prescription status of the medications is unknown.

1. Non-pharmaceutical substances – 224 substance occurrences . Ethanol 208 (92.3%) of occurrences

2. Pharmaceutical substances – 5,602 substance occurrences . Analgesics – 475 occurrences o Opioids (144); with APAP (86) . Anticonvulsants (other than gabapentin) = 233 occurrences . Antidepressants = 672 occurrences . Antihistamines = 186 occurrences . Cardiovascular drugs = 384 occurrences . Muscle relaxants = 153 occurrences . Hormones (includes diabetic drugs) = 157 occurrences . Sedative hypnotic/antipsychotic agents = 721 occurrences o Benzodiazepines = 291 occurrences . Stimulants and street drugs = 114 occurrences o Amphetamine/methamphetamine = 57 occurrences o Heroin = 15 occurrences

Appendix 5 - Additional data

Table 1. All claims ALL FILLS 2016 2017 2018 2019 Total Product Patients Claims Patients Claims Patients Claims Patients Claims Patients Claims Gabapentin GABAPENTIN CAP 100MG 1606 4901 1662 4933 1811 5553 1878 5225 5384 20612 Gabapentin GABAPENTIN CAP 300MG 5401 21521 5448 21667 5965 23659 6165 21775 15034 88622 Gabapentin GABAPENTIN CAP 400MG 861 3782 839 3745 978 4305 1109 4136 2591 15968 Gabapentin GABAPENTIN SOL 250/5ML 217 1103 226 1304 281 1580 273 1398 590 5385 Gabapentin GABAPENTIN SOL 300/6ML . . . . 1 1 . . 1 1 Gabapentin GABAPENTIN TAB 600MG 2587 13497 2550 13400 2991 15412 3441 14541 6932 56850 Gabapentin GABAPENTIN TAB 800MG 1477 8682 1548 9392 2032 11408 2415 11659 4082 41141 Gabapentin NEURONTIN CAP 100MG 1 5 ...... 1 5 Gabapentin NEURONTIN CAP 300MG 3 37 3 37 1 10 1 9 3 93 Gabapentin NEURONTIN SOL 250/5ML 2 19 2 18 2 21 2 22 2 80 Gabapentin NEURONTIN TAB 800MG 2 15 1 8 1 8 1 7 2 38 Gabapentin (Bulk) GABAPENTIN POW 1 1 1 4 . . . . 2 5 Gabapentin (Once-Daily) GRALISE TAB 600MG 3 29 5 26 3 32 4 24 6 111 Gabapentin Enacarbil HORIZANT TAB 600MG ER 2 5 1 10 3 17 1 9 5 41 Total Total 9884 53597 9991 54544 11393 62006 12447 58805 24612 228952 (Only products with claims/utilization are shown)

Table 2. FFS claims 2016 2017 2018 2019 Total Product Patients Claims Patients Claims Patients Claims Patients Claims Patients Claims GABAPENTIN CAP 100MG 529 1451 556 1441 622 1715 833 2010 2123 6617 GABAPENTIN CAP 300MG 1928 6390 1935 6359 2554 8123 3203 9259 7218 30131 GABAPENTIN CAP 400MG 319 1101 304 1016 432 1458 604 1811 1307 5386 GABAPENTIN SOL 250/5ML 60 270 73 348 86 526 100 501 209 1645 GABAPENTIN TAB 600MG 982 4018 925 3890 1452 5854 2011 6928 3804 20690 GABAPENTIN TAB 800MG 530 2290 547 2202 1043 4308 1470 5765 2470 14565 NEURONTIN CAP 300MG 1 2 ...... 1 2 GABAPENTIN POW 1 1 ...... 1 1 2016 2017 2018 2019 Total Product Patients Claims Patients Claims Patients Claims Patients Claims Patients Claims GRALISE TAB 600MG ...... 1 1 1 1 HORIZANT TAB 600MG ER . . . . 1 1 . . 1 1 Total 3695 15523 3697 15256 5099 21985 6690 26275 12999 79039

Table 3. Pediatric claims

ALL PEDIATRIC CLAIMS 2016 2017 2018 2019 ALL AGENT PRODUCT CLAIMS PATIENTS CLAIMS PATIENTS CLAIMS PATIENTS CLAIMS PATIENTS CLAIMS PATIENTS GABAPENTIN CAP Gabapentin 100MG 589 163 680 200 858 241 605 175 2,732 564 GABAPENTIN CAP Gabapentin 300MG 476 128 499 156 583 175 491 146 2,049 453 GABAPENTIN CAP Gabapentin 400MG 143 27 160 33 170 36 83 24 556 77 GABAPENTIN SOL Gabapentin 250/5ML 789 154 942 157 1194 209 1047 196 3,972 402 GABAPENTIN TAB Gabapentin 600MG 224 29 180 36 156 37 102 26 662 89 GABAPENTIN TAB Gabapentin 800MG 38 8 34 13 37 7 26 6 135 22 NEURONTIN SOL Gabapentin 250/5ML 12 1 14 1 13 1 12 1 51 1 Total 2271 448 2509 513 3011 617 2366 505 10,157 1,323

FFS PEDIATRIC CLAIMS 2016 2017 2018 2019 ALL AGENT PRODUCT CLAIMS PATIENTS CLAIMS PATIENTS CLAIMS PATIENTS CLAIMS PATIENTS CLAIMS PATIENTS GABAPENTIN CAP Gabapentin 100MG 111 33 118 42 159 40 137 34 525 107 GABAPENTIN CAP Gabapentin 300MG 56 17 52 24 89 31 106 39 303 92 GABAPENTIN CAP Gabapentin 400MG 15 6 38 6 20 7 4 3 77 15 GABAPENTIN SOL Gabapentin 250/5ML 165 37 253 50 403 66 362 65 1,183 131 GABAPENTIN TAB Gabapentin 600MG 23 4 26 6 34 9 31 11 114 22

FFS PEDIATRIC CLAIMS 2016 2017 2018 2019 ALL AGENT PRODUCT CLAIMS PATIENTS CLAIMS PATIENTS CLAIMS PATIENTS CLAIMS PATIENTS CLAIMS PATIENTS GABAPENTIN TAB Gabapentin 800MG 8 3 2 1 4 2 5 1 19 7 Total 378 88 489 115 709 142 645 138 2,221 323

Table 4. Number of pediatric patients by age and diagnosis codes

DX DESCRIPTION A EPILEPSY N POSTHERPETIC NEURALGIA R RESTLESS LEG SYNDROME B ALCOHOL MISUSE C DRUG DEPENDENCE D DRUG ABUSE E POISONING (any substance) G ACCIDENTAL POISONING (subset of poisoning) Definitions/list of diagnosis codes included in each category available on request.

GABAPENTIN ALL PEDIATRIC PATIENTS

TOTAL PATIENTS 2016-2019 AGE* M F Total DX A PERCENT DX R PERCENT DX B PERCENT DX C PERCENT DX D PERCENT DX E PERCENT DX G PERCENT 0 27 15 42 10 23.8% . . . . 5 11.9% ......

1 19 7 26 6 23.1% . . . . 1 3.8% ......

2 23 20 43 15 34.9% 1 2.3% . . 1 2.3% ......

3 16 15 31 14 45.2% . . . . 1 3.2% ......

4 19 13 32 9 28.1% ......

5 23 23 46 11 23.9% 1 2.2% ...... 1 2.2%

6 15 14 29 6 20.7% 1 3.4% ......

7 21 13 34 6 17.6% ......

8 27 17 44 9 20.5% ...... 1 2.3% . .

9 22 18 40 5 12.5% ......

10 24 24 48 9 18.8% . . . . 1 2.1% 1 2.1% . . . .

11 47 26 73 12 16.4% ...... 1 1.4% 1 1.4% 1 1.4%

12 43 32 75 15 20.0% . . . . 1 1.3% ......

GABAPENTIN ALL PEDIATRIC PATIENTS

TOTAL PATIENTS 2016-2019 AGE* M F Total DX A PERCENT DX R PERCENT DX B PERCENT DX C PERCENT DX D PERCENT DX E PERCENT DX G PERCENT 13 39 50 89 8 9.0% 1 1.1% . . 2 2.2% 6 6.7% 4 4.5% 1 1.1%

14 52 74 126 8 6.3% . . . . 4 3.2% 7 5.6% 2 1.6% 4 3.2%

15 57 90 147 12 8.2% . . 7 4.8% 5 3.4% 17 11.6% 12 8.2% 4 2.7%

16 70 118 188 9 4.8% 1 0.5% 10 5.3% 8 4.3% 18 9.6% 10 5.3% 2 1.1%

17 80 130 210 13 6.2% 3 1.4% 7 3.3% 16 7.6% 25 11.9% 11 5.2% 4 1.9%

TOTAL 624 699

* Age at first claim.

GABAPENTIN FFS PEDIATRIC PATIENTS

TOTAL PATIENTS 2016-2019 AGE* M F Total DX A PERCENT DX R PERCENT DX B PERCENT DX C PERCENT DX D PERCENT DX E PERCENT DX G PERCENT 0 12 4 16 7 43.8% . . . . 3 18.8% ......

1 6 3 9 4 44.4% . . . . 1 11.1% ......

2 9 11 20 13 65.0% 1 5.0% . . 1 5.0% ......

3 7 6 13 8 61.5% . . . . 1 7.7% ......

4 6 5 11 6 54.5% ......

5 7 8 15 10 66.7% 1 6.7% ......

6 3 6 9 3 33.3% 1 11.1% ......

7 6 9 15 6 40.0% ......

8 . 2 2 1 50.0% ......

9 7 4 11 5 45.5% ...... 1 9.1% . .

10 6 5 11 4 36.4% ......

11 11 6 17 5 29.4% . . . . 1 5.9% 1 5.9% 1 5.9% 1 5.9%

12 7 8 15 9 60.0% ......

13 8 12 20 6 30.0% 1 5.0% . . . . 1 5.0% 1 5.0% 1 5.0%

14 8 16 24 3 12.5% ...... 3 12.5% 1 4.2% 2 8.3%

15 15 21 36 5 13.9% . . 1 2.8% 2 5.6% 5 13.9% 4 11.1% 2 5.6%

16 9 29 38 4 10.5% 1 2.6% 3 7.9% 1 2.6% 5 13.2% 2 5.3% 1 2.6%

17 24 17 41 2 4.9% 1 2.4% 6 14.6% 9 22.0% 12 29.3% 4 9.8% 2 4.9%

GABAPENTIN FFS PEDIATRIC PATIENTS

TOTAL PATIENTS 2016-2019 AGE* M F Total DX A PERCENT DX R PERCENT DX B PERCENT DX C PERCENT DX D PERCENT DX E PERCENT DX G PERCENT TOTAL 151 172

* Age at first claim.

Table 5. Diagnosis codes submitted (adult and pediatric patients) A EPILEPSY/SEIZURES N POSTHERPETIC NEURALGIA R RESTLESS LEG SYNDROME B ALCOHOL MISUSE C DRUG DEPENDENCE D DRUG ABUSE E POISONING (any substance) G ACCIDENTAL POISONING (subset of poisoning) Definitions/list of diagnosis codes included in each category available on request.

Gabapentin - ALL CLAIMS 2016-2019

AGENT PRODUCT CLAIMS PATIENTS DX A DX N DX R* DX B DX C DX D DX E DX G

Gabapentin GABAPENTIN 20,612 5,384 444 8.2% 4 0.07% 137 2.54% 420 7.80% 790 14.67% 552 10.25% 222 4.12% 131 2.43% CAP 100MG Gabapentin GABAPENTIN 88,622 15,034 1,238 8.2% 15 0.10% 413 2.75% 1,526 10.15% 3,147 20.93% 2,216 14.74% 632 4.20% 483 3.21% CAP 300MG Gabapentin GABAPENTIN 15,968 2,591 312 12.0% 7 0.27% 96 3.71% 365 14.09% 839 32.38% 599 23.12% 210 8.11% 158 6.10% CAP 400MG Gabapentin GABAPENTIN 5,385 590 163 27.6% . . 6 1.02% 17 2.88% 28 4.75% 16 2.71% 7 1.19% 9 1.53% SOL 250/5ML Gabapentin GABAPENTIN 1 1 ...... SOL 300/6ML Gabapentin GABAPENTIN 56,850 6,932 738 10.6% 14 0.20% 236 3.40% 877 12.65% 2,153 31.06% 1,508 21.75% 441 6.36% 336 4.85% TAB 600MG Gabapentin GABAPENTIN 41,141 4,082 484 11.9% 8 0.20% 162 3.97% 556 13.62% 1,641 40.20% 1,224 29.99% 354 8.67% 275 6.74% TAB 800MG Gabapentin NEURONTIN 5 1 ...... CAP 100MG Gabapentin NEURONTIN 93 3 1 33.3% ...... 1 33.33% . . 1 33.33% . . CAP 300MG Gabapentin NEURONTIN 80 2 ...... SOL 250/5ML Gabapentin NEURONTIN 38 2 1 50.0% ...... 1 50.00% . . TAB 800MG Gabapentin GABAPENTIN 5 2 ...... 1 50.00% ...... (Bulk) POW Gabapentin GRALISE TAB 111 6 ...... 1 16.67% . . 1 16.67% . . (Once- 600MG Daily) Gabapentin HORIZANT 41 5 ...... Enacarbil TAB 600MG ER TOTALS 228,952 24,612 2,137 8.7% 26 0.11% 678 2.75% 2,378 9.66% 5,221 21.21% 3,739 15.19% 1,078 4.38% 833 3.38%

**None of these claims are in the time period Oct 1, 2018 - Sep 30, 2019 51

Gabapentin – FFS 2016-2019

AGENT PRODUCT CLAIMS PATIENTS DX A DX N DX R* DX B DX C DX D DX E DX G

Gabapentin GABAPENTIN 6,617 2,123 249 11.73% 4 0.19% 84 3.96% 264 12.44% 423 19.92% 339 15.97% 109 5.13% 82 3.86% CAP 100MG Gabapentin GABAPENTIN 30,131 7,218 755 10.46% 9 0.12% 299 4.14% 1,085 15.03% 2,020 27.99% 1,605 22.24% 369 5.11% 331 4.59% CAP 300MG Gabapentin GABAPENTIN 5,386 1,307 211 16.14% 5 0.38% 67 5.13% 268 20.51% 537 41.09% 446 34.12% 127 9.72% 104 7.96% CAP 400MG Gabapentin GABAPENTIN 1,645 209 101 48.33% . . 5 2.39% 13 6.22% 17 8.13% 10 4.78% 5 2.39% 7 3.35% SOL 250/5ML Gabapentin GABAPENTIN 20,690 3,804 475 12.49% 10 0.26% 168 4.42% 638 16.77% 1,462 38.43% 1,134 29.81% 270 7.10% 237 6.23% TAB 600MG Gabapentin GABAPENTIN 14,565 2,470 345 13.97% 6 0.24% 126 5.10% 429 17.37% 1,194 48.34% 987 39.96% 243 9.84% 210 8.50% TAB 800MG Gabapentin NEURONTIN 2 1 1 100% ...... 1 100% . . CAP 300MG Gabapentin GABAPENTIN 1 1 ...... (Bulk) POW Gabapentin GRALISE 1 1 ...... (Once-Daily) TAB 600MG Gabapentin HORIZANT 1 1 ...... Enacarbil TAB 600MG ER TOTALS 79,039 12,999 1,421 10.93% 21 0.16% 521 4.01% 1,831 14.09% 3,752 28.86% 2,966 22.82% 734 5.65% 631 4.85%

*None of these claims are in the time period Oct 1, 2018 - Sep 30, 2019

Table 6. Prescribers

Specialty ALL Specialty FFS ALL Credentials FFS Credentials Specialty RXs Specialty RXs Credentials RXs Credentials RXs Family Practice 75324 Family Practice 29749 Physician 107174 Physician 36476 Internal Medicine 23504 Internal Medicine 8244 Nurse Practitioner 41574 Nurse Practitioner 14480 Psychiatry 6996 Emergency Medicine 2860 Osteopath 23496 Osteopath 9423 Pediatrics 6779 Pediatrics 1976 QMB-Only Prov 7559 QMB-Only Prov 1587 Physical Medicine and R 6200 Physical Medicine and R 1734 Podiatrist 736 Cert Nurse Midwife 285 Emergency Medicine 6011 Psychiatry 1688 Cert Nurse Midwife 677 Registered Nurse 254 Neurology 5619 Neurology 1014 Registered Nurse 528 Podiatrist 162 Anesthesiology 3768 General Practice 1004 Physical Therapist 170 Physical Therapist 100 General Practice 1883 Obstetrics-Gynecology 769 Cert Social Worker 147 Cert Social Worker 30 Obstetrics-Gynecology 1751 Anesthesiology 549 Psychologist 54 Nurse Anesthetist 11 Pulmonary Diseases 1299 Pulmonary Diseases 466 Group Practice 43 Physician Assistant 5 Child Psychiatry 1257 General Preventive Medi 324 Physician Assistant 38 Oral Surgeons 4 General Preventive Medi 1071 Orthopedic Surgery 214 Dentist 25 Dentist 3 Orthopedic Surgery 869 Child Psychiatry 122 Nurse Anesthetist 11 LPN 1 Rheumatology 699 Pediatric Neurology 106 Oral Surgeons 9 Psychologist 1 Oncology 424 Infectious Diseases 98 LPN 5 Unknown 17628 Infectious Diseases 404 General Surgery 86 Optometrist 4 Pediatric Neurology 383 Rheumatology 83 Unknown 53536 General Surgery 355 Hematology 66

Specialty ALL Specialty FFS ALL Credentials FFS Credentials Hematology 343 Oncology 56 Gastroenterology 151 Cardiology 42 Cardiology 148 Nephrology 40 Nephrology 147 Gastroenterology 38 Neurological Surgery 140 Ophthalmology 30 Endocrinology 106 Geriatrics 28 Geriatrics 103 Plastic Surgery 23 Gynecology 93 Dermatology 22 Otorhinolaryngology 92 Otorhinolaryngology 22 Dermatology 87 Radiology 20 Radiology 82 Neurological Surgery 19 Plastic Surgery 75 Urology 15 Urology 72 Cardiovascular Diseases 12 Pathology 67 Gynecology 10 Ophthalmology 62 Pathology 9 Cardiovascular Diseases 59 Radiation Oncology 9 Neonatology 50 Neonatology 6 Diagnostic Radiology 49 Diagnostic Radiology 5 Radiation Oncology 46 Cardiovascular Surgery 4 Neuropathology 30 Hand Surgery 3 Neuroradiology 27 Pediatric Cardiology 3 Cardiovascular Surgery 24 Thoracic Surgery 3 Hand Surgery 18 Colon and Rectal Surger 2 Thoracic Surgery 18 Endocrinology 2 Diabetes 13 Diabetes 1 Oncology Surgery 11 Oncology Surgery 1 Pediatric Surgery 8 Unknown 34608 Aerospace Medicine 7 Allergy 5 Colon and Rectal Surger 5 Pediatric Cardiology 4 Occupational Medicine 3 Clinical Pathology 1 Unknown 103798

Appendix 6 – Exploring potential problematic use

Table 1. Number of patients (ALL) by number of prescriptions (in last year) with select diagnoses Gabapentin fills (ALL) from Oct 1, 2018 - Sep 30, 2019 A N B C D E G ACCIDENTAL POISONING Number POSTHERPETIC RESTLESS LEG ALCOHOL DRUG POISONING (subset of of Rxs Patients EPILEPSY NEURALGIA SYNDROME MISUSE DEPENDENCE DRUG ABUSE (any substance) poisoning) 1 3134 157 4 49 298 529 416 81 61 2 1773 90 1 47 186 429 306 54 42 3 1294 92 1 24 147 343 246 37 29 4 1007 82 2 23 131 271 195 38 28 5 867 62 1 26 108 260 186 31 16 6 789 61 1 20 76 208 137 31 22 7 731 53 . 13 61 210 140 25 26 8 603 40 4 21 54 142 93 24 15 9 527 48 . 10 44 124 72 16 10 10 539 43 . 16 41 122 69 18 12 11 563 47 1 15 31 95 52 8 7 12 698 73 . 18 40 130 54 16 14 13 433 41 3 7 22 100 49 10 4 14 194 20 . 6 18 47 19 5 6 15 81 5 . 1 7 21 16 4 4 16 42 3 . . 6 13 5 1 2 17 24 3 . 1 2 8 2 . 1 18 29 5 . 1 4 9 8 3 2 19 25 4 . 2 2 11 7 1 1 20 17 1 . 1 . 6 4 1 . 21 12 1 . . 3 1 3 1 1 22 14 1 . . 2 5 1 . . 23 9 . . . 2 3 2 2 . 24 15 2 . . . 1 . . . 25 5 3 . . . 1 . 1 . 26 11 3 . . 1 4 1 1 1 27 4 1 ...... 28 2 ...... 29 2 2 . 1 . 1 . 1 . 30 1 ...... 31 1 ...... 32 1 . . . 1 1 1 . . 33 2 1 ...... 35 1 ...... 36 1 ...... 38 2 ...... 42 1 . . . . 1 . . . 47 2 . . . . . 1 . . 51 1 ...... 52 1 ...... 78 1 ...... 104 1 1 ...... Total 13460

Table 2. Number of patients (ALL) by number of prescriptions (in last year) that fulfil select criteria Gabapentin fills (ALL) from Oct 1, 2018 - Sep 30, 2019 Concurrent Concurrent Concurrent >1 >1 Patients with >400 pregabalin Concurrent Concurrent opioid and "muscle Concurrent Concurrent Gabapentin Pharmacy >1 Prescriber >3600mg/day days’ (within 30 opioid benzodiazepine benzo relaxant" hypnotic opioid+benzo+muscle Number (within 30 (within (GABA/Opioid) (excluding supply days)* (within 30 (within 30 (within 30 (within 30 (within 30 relaxant+hypnotic of Rxs Patients days) 30 days) within 30 days >3600mg/day* solutions)◊ (year)♦ >once days) days) days) days) days) (within 30 days) 1 3134 . . 462 6 6 . 87 779 487 187 474 101 7 2 1773 720 192 321 6 6 . 57 495 310 111 354 94 9 3 1294 784 300 306 4 4 . 45 420 269 106 273 79 5 4 1007 758 388 262 4 4 . 31 362 257 104 263 73 10 5 867 715 394 256 7 6 . 57 353 239 116 228 61 7 6 789 686 436 284 4 4 . 25 359 253 126 233 71 7 7 731 657 570 267 6 6 . 30 342 217 103 240 81 5 8 603 559 390 230 5 5 . 28 287 195 100 229 60 8 9 527 513 486 238 8 8 . 21 295 191 108 205 59 14 10 539 532 464 256 8 8 . 32 315 203 126 215 63 5 11 563 561 536 247 11 10 . 22 313 231 131 216 64 10 12 698 698 756 321 10 10 . 25 407 269 178 276 86 22 13 433 433 578 188 8 8 1 15 247 203 123 192 65 17 14 194 194 478 89 8 8 132 4 106 73 41 85 28 3 15 81 81 238 45 2 2 65 3 50 30 23 43 9 1 16 42 42 164 23 . . 31 2 25 21 15 22 7 3 17 24 24 108 15 3 3 16 1 16 12 7 10 2 1 18 29 29 220 11 2 2 20 3 12 10 6 10 1 . 19 25 25 186 9 . . 19 1 11 14 7 11 7 1 20 17 17 126 8 . . 12 1 9 2 2 8 1 . 21 12 12 114 4 2 2 11 1 4 5 2 4 3 . 22 14 14 108 8 . . 12 1 8 4 2 2 1 . 23 9 9 82 3 . . 8 . 4 7 3 3 3 1 24 15 15 96 4 . . 13 . 6 9 3 8 2 1 25 5 5 58 1 . . 3 . 2 2 . 1 . . 26 11 11 136 7 . . 9 . 8 6 5 5 2 2 27 4 4 8 3 . . 3 . 4 3 3 3 1 . 28 2 2 2 1 . . 1 1 2 1 1 . . . 29 2 2 . 2 . . 2 . 2 2 2 1 . . 30 1 1 . 1 . . 1 . 1 . . . . . 31 1 1 32 . 1 1 . . . . . 1 . . 32 1 1 48 1 . . 1 . 1 . . 1 . . 33 2 2 106 1 . . 2 . 1 . . 1 . . 35 1 1 2 1 . . . . 1 1 1 . . . 36 1 1 ...... 1 . 38 2 2 12 2 . . . . 2 2 1 1 1 1 42 1 1 28 ...... 1 . . . . 47 2 2 14 1 . . . 1 1 1 . 1 . . 51 1 1 ...... 1 . . . . . Gabapentin fills (ALL) from Oct 1, 2018 - Sep 30, 2019 Concurrent Concurrent Concurrent >1 >1 Patients with >400 pregabalin Concurrent Concurrent opioid and "muscle Concurrent Concurrent Gabapentin Pharmacy >1 Prescriber >3600mg/day days’ (within 30 opioid benzodiazepine benzo relaxant" hypnotic opioid+benzo+muscle Number (within 30 (within (GABA/Opioid) (excluding supply days)* (within 30 (within 30 (within 30 (within 30 (within 30 relaxant+hypnotic of Rxs Patients days) 30 days) within 30 days >3600mg/day* solutions)◊ (year)♦ >once days) days) days) days) days) (within 30 days) 52 1 1 . 1 . . 1 . 1 1 1 1 . . 78 1 1 . 1 . . 1 . 1 . . . . . 104 1 1 . . . . 1 . . 1 . . 1 . Total 13460 *Used single prescription to calculate this: (Quantity/day supply) x strength of formulation; this does not capture dosing of patients that received multiple prescriptions overlapping/different strength formulations on separate prescription (underestimate). ◊ It was unclear whether the quantity in the claims data is the actual mL amount. ♦This would be an overestimate if patients received multiple prescriptions overlapping/different strength formulations on separate prescriptions because total days’ supply would be counted for each.

*Definition for opioid *Definition for benzodiazepine *Definition for muscle relaxant *Definition for Hypnotics (Non- Benzodiazepines, Non-Barbiturates) Codeine Alprazolam tizanidine Doxepin Hydrocodone Chlordiazepoxide baclofen Eszopiclone Hydromorphone Clobazam carisoprodol Ramelteon Levorphanol Clonazepam cyclobenzaprine Suvorexant Meperidine Clorazepate orphenadrine Tasimelteon Morphine Diazepam methocarbamol Zaleplon Oxycodone Estazolam chlorzoxazone Zolpidem Oxymorphone Flurazepam metaxalone Tapentadol Lorazepam Tramadol Midazolam Fentanyl transdermal patches Oxazepam Hydrocodone ER Quazepam Hydromorphone ER Temazepam Methadone Triazolam Morphine Sulfate ER Oxycodone ER Oxymorphone ER Tapentadol ER Tramadol ER

Table 3. Number of patients (FFS) by number of prescriptions (in last year) with select diagnoses

Gabapentin fills (FFS) from Oct 1, 2018 - Sep 30, 2019 A N B C D E G ACCIDENTAL POISONING POSTHERPETIC RESTLESS LEG ALCOHOL DRUG POISONING (subset of Number of Rxs Patients EPILEPSY NEURALGIA SYNDROME MISUSE DEPENDENCE DRUG ABUSE (any substance) poisoning) 1 2104 145 2 47 281 496 404 70 57 2 1144 79 1 41 166 391 300 47 39 3 796 62 1 19 128 297 218 32 30 4 603 52 2 20 108 219 165 28 25 5 508 44 1 22 92 208 156 24 13 6 387 44 1 19 58 147 112 19 19 7 345 45 . 16 42 149 106 17 17 8 270 31 2 12 39 105 80 13 13 9 210 25 1 9 32 78 54 7 6 10 189 25 . 12 29 80 50 7 9 11 181 28 . 13 19 54 44 2 4 12 213 39 . 12 30 77 35 11 10 13 115 26 3 6 12 47 31 3 3 14 64 13 . 4 10 23 13 2 3 15 24 3 . 1 5 9 8 2 2 16 12 2 . . 4 5 4 . 1 17 8 1 . . 2 3 . . . 18 6 3 . . 2 6 5 2 1 19 10 2 . 1 1 4 5 . . 20 7 1 . 1 . 5 4 1 . 21 3 1 . . 2 . 3 . . 22 3 1 . . 1 1 . . . 23 2 1 ...... 24 6 3 . . . 2 . 1 . 25 2 1 ...... 26 2 1 . . . 1 . . 1 27 3 1 ...... 29 3 2 . 1 . 1 . 1 . 33 1 1 ...... 36 1 ...... 47 1 ...... 51 1 ...... 52 1 ...... 78 1 ...... 104 1 1 ...... Total 7227

Table 4. Number of patients (FFS) by number of prescriptions (in last year) that fulfil select criteria Gabapentin fills (FFS) from Oct 1, 2018 - Sep 30, 2019 Concurrent Concurrent pregabalin Concurrent Concurrent opioid+benzo >1 >1 Prescriber (within 30 Concurrent Concurrent opioid and "muscle Concurrent +muscle Gabapentin >1 Pharmacy (GABA/Opioi days)* on opioid benzodiazepi benzo relaxant" hypnotic relaxant+hyp Number of (within 30 (within 30 d) within 30 >3600mg/ >400 days’ >one (within 30 ne (within 30 (within 30 (within 30 within 30 notic (within Rxs Patients days) days) days day* supply (year) occasion days)* days)* days) days)* days)* 30 days) 1 2104 . . 240 6 . 48 404 315 92 308 56 3 2 1144 534 170 151 5 . 33 248 200 58 217 55 4 3 796 534 212 139 2 . 22 209 144 48 153 39 . 4 603 482 266 129 3 . 22 190 147 48 157 41 4 5 508 456 272 119 5 . 32 165 113 44 124 28 4 6 387 347 270 120 1 . 14 154 115 51 103 25 . 7 345 317 336 110 3 . 15 143 100 49 107 29 2 8 270 253 190 84 3 . 18 108 89 41 93 26 . 9 210 205 268 76 5 . 9 97 66 30 75 12 2 10 189 187 260 78 1 . 11 95 65 36 66 19 2 11 181 180 278 76 2 . 5 97 68 39 64 17 4 12 213 213 306 82 1 . 7 106 63 35 78 16 3 13 115 115 180 37 3 . 3 54 49 25 49 13 4 14 64 64 156 26 2 45 2 34 27 17 27 8 . 15 24 24 92 9 . 15 1 12 7 4 13 1 . 16 12 12 50 7 . 8 . 9 5 5 6 . . 17 8 8 28 6 2 2 . 6 4 1 3 . . 18 6 6 54 1 . 3 2 1 1 1 2 . . 19 10 10 118 3 . 6 1 5 4 2 4 3 . 20 7 7 70 5 . 4 . 5 1 1 4 . . 21 3 3 40 1 . 3 . 1 . . . 1 . 22 3 3 20 1 . 2 . 1 . . . . . 23 2 2 . . . 1 . . 1 . . . . 24 6 6 82 4 . 5 . 5 3 3 4 1 . 25 2 2 . . . 1 . 1 1 . 1 . . 26 2 2 . 2 . . . 2 1 1 2 . . 27 3 3 8 3 . 2 . 3 2 2 3 . . 29 3 3 . 3 . 3 . 3 2 2 1 . . 33 1 1 . 1 . 1 . 1 . . 1 . . 36 1 1 ...... 1 . 47 1 1 ...... 1 . . . . 51 1 1 . . . . . 1 . . . . . 52 1 1 . 1 . 1 . 1 1 1 1 . . 78 1 1 . 1 . 1 . 1 . . . . . 104 1 1 . . . 1 . . 1 . . 1 . Total 7227

*Used single prescription to calculate this: (Quantity/day supply) x strength of formulation; this would not capture dosing of patients that received multiple prescriptions overlapping/different strength formulations on separate prescription (underestimate). ◊It was unclear whether the quantity in the claims data is the actual mL amount etc. ♦This would be an overestimate if patients received multiple prescriptions overlapping/different strength formulations on separate prescriptions.

Table 5. Prescribers of patients with >400 days’ supplied♦ from Oct 1, 2018 - Sep 30, 2019 Specialty ALL Specialty FFS ALL Credentials FFS Credentials Specialty RXs Specialty RXs Credentials RXs Credentials RXs Family Practice 5132 Family Practice 1688 Physician 7235 Physician 1965 Internal Medicine 1400 Internal Medicine 570 Nurse Practitioner 2996 Nurse Practitioner 695 Psychiatry 597 Physical Medicine and R 144 Osteopath 1596 Osteopath 641 Physical Medicine and R 562 Pediatrics 140 QMB-Only Prov 717 QMB-Only Prov 70 Neurology 447 Emergency Medicine 89 Cert Nurse Midwife 39 Cert Nurse Midwife 31 Pediatrics 443 Psychiatry 59 Registered Nurse 11 Unknown 504 Anesthesiology 222 Pulmonary Diseases 53 Physical Therapist 5 Emergency Medicine 196 Child Psychiatry 32 Podiatrist 3 Pulmonary Diseases 172 Neurology 27 Cert Social Worker 1 Child Psychiatry 125 Anesthesiology 25 Unknown 2799 Rheumatology 115 General Practice 21 Obstetrics-Gynecology 73 Obstetrics-Gynecology 10 General Preventive Medi 72 Orthopedic Surgery 7 General Practice 54 Rheumatology 6 Neonatology 39 Ophthalmology 5 Orthopedic Surgery 23 General Preventive Medi 4 Pediatric Neurology 18 Gastroenterology 3 Oncology 14 Geriatrics 2 General Surgery 9 Pediatric Neurology 2 Ophthalmology 5 Neurological Surgery 1 Gastroenterology 3 Unknown 1309 Geriatrics 2 Gynecology 2 Otorhinolaryngology 2 Cardiology 1 Neurological Surgery 1 Unknown 6510 ♦This would be an overestimate if patients received multiple prescriptions overlapping/different strength formulations on separate prescriptions.

Table 6. Diagnosis codes submitted for potential inappropriate gabapentin use/prescribing/patients at increased risk for adverse outcomes

NUMBER OF PATIENTS WITH THESE DX Gabapentin fills (ALL) from Oct 1, 2018 - Sep 30, 2019

A N B C D E G ACCIDENTAL POISONING POISONING RESTLESS LEG POSTHERPETIC ALCOHOL DRUG (any (subset of Any dx EPILEPSY SYNDROME NEURALGIA MISUSE DEPENDENCE DRUG ABUSE substance) poisoning)

>1 Prescriber (GABA/Opioid) within 30 days 1622 463 158 9 420 998 609 205 151

>1 Pharmacy (within 30 days 1140 272 86 3 350 830 627 171 137

Patients with >3600mg/day* 55 21 3 1 7 42 26 9 9

Patients with >400 days’ supply (year)♦ 184 49 14 0 39 127 75 31 19

PATIENTS WITH Concurrent opioid (within 30 days)* 2065 562 204 11 520 1259 753 247 192

PATIENTS WITH Concurrent PREGABALIN(within 30 days)* 258 70 23 1 63 181 119 32 29

PATIENTS WITH Concurrent benzodiazepine (within 30 days 1724 571 117 4 472 1062 690 259 202

Patient with concurrent opioid and benzo (within 30 days) 777 281 61 2 163 483 260 108 87

Patient with concurrent muscle relaxant (within 30 days) 1544 428 148 12 387 940 582 189 145

Patient with concurrent hypnotic within 30 days)* 439 114 41 2 96 285 161 80 59

Patient with concurrent opioid+benzo+muscle relaxant+hypnotic 63 25 7 0 9 38 17 10 6

*Used single prescription to calculate this: (Quantity/day supply) x strength of formulation; this would not capture dosing of patients that received multiple prescriptions overlapping/different strength formulations on separate prescription (underestimate). ♦This would be an overestimate if patients received multiple prescriptions overlapping/different strength formulations on separate prescriptions.

References

1. Centers for Disease Control and Prevention (CDC). Drug overdose Deaths. https://www.cdc.gov/drugoverdose/data/statedeaths.html. Accessed October 8, 2019. 2. Scholl L, Seth P, Kariisa M, Wilson N, Baldwin G. Drug and Opioid-Involved Overdose Deaths — United States, 2013–2017. MMWR Morb Mortal Wkly Rep 2019;67:1419–1427. DOI: http://dx.doi.org/10.15585/mmwr.mm675152e1external 3. Centers for Disease Control and Prevention (CDC). Drug Overdose All Drugs. https://www.cdc.gov/drugoverdose/data/nonfatal/drugs-overall.html. Accessed October 8, 2019. 4. Hedegaard H, Bastian BA, Trinidad JP, Spencer M, Warner M. Drugs most frequently involved in drug overdose deaths: United States, 2011–2016. National Vital Statistics Reports; vol 67 no 9. Hyattsville, MD: National Center for Health Statistics. 2018. Available from: https://www.cdc.gov/nchs/data/nvsr/nvsr67/nvsr67_09-508.pdf. 5. Warner M, Trinidad JP, Bastian BA, Miniño AM, Hedegaard H. Drugs most frequently involved in drug overdose deaths: United States, 2010–2014. National Vital Statistics Reports; vol 65 no 10. Hyattsville, MD: National Center for Health Statistics. 2016. Available from: https://www.cdc.gov/nchs/data/nvsr/nvsr65/nvsr65_10.pdf. 6. Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain - United States, 2016. MMWR Recommendations and reports : Morbidity and mortality weekly report Recommendations and reports. 2016;65(1):1-49. 7. Dowell D, Haegerich T, Chou R. No Shortcuts to Safer Opioid Prescribing. New England Journal of Medicine. 2019;380(24):2285-2287. 8. Drug Enforcement Administration. Gabapentin (Neurontin®). October 2018. https://www.deadiversion.usdoj.gov/drug_chem_info/gabapentin.pdf. Accessed October 8, 2019. 9. Smith RV, Havens JR, Walsh SL. Gabapentin misuse, abuse and diversion: a systematic review. Addiction (Abingdon, England). 2016;111(7):1160-1174. 10. Evoy KE, Morrison MD, Saklad SR. Abuse and Misuse of Pregabalin and Gabapentin. Drugs. 2017;77(4):403-426. 11. Neurontin Prescribing Information. In. www.Accessdata.FDA.gov: FDA; 2017. 12. Lexicomp Online, Gabapentin (Lexi-Drugs), Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2019. Accessed October 10, 2019. 13. Ahmed S, Bachu R, Kotapati P, et al. Use of Gabapentin in the Treatment of Substance Use and Psychiatric Disorders: A Systematic Review. Frontiers in psychiatry. 2019;10:228. 14. Bonnet U, Scherbaum N. How addictive are gabapentin and pregabalin? A systematic review. European Neuropsychopharmacology. 2017;27(12):1185-1215. 15. McNamara JO. Pharmacotherapy of the Epilepsies. In: Brunton LL, Chabner BA, Knollmann BC, eds. Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 12e. New York, NY: McGraw-Hill Education; 2015. 16. Taylor CP. Mechanisms of action of gabapentin. Revue neurologique. 1997;153 Suppl 1:S39-45. 17. Division DEADC. Gabapentin. https://www.deadiversion.usdoj.gov/drug_chem_info/gabapentin.pdf#search=gabapentin. Published 2018. Accessed June 18, 2019. 18. Michigan Department of Licensing & Regulatory Affairs Revises Controlled Substance Rules. Jan, 2019 https://healthlawcenterplc.com/michigan-department-of-licensing-regulatory-affairs- revises-controlled-substance-rules/. Accessed October 9, 2019. 19. Michigan Acadamy of Family Physicians (MAFP) News. Controlled Substance Administrative Rule Changes in Effect as of Jan. 4 https://www.mafp.com/news/controlled-substance- administrative-rule-changes-in-effect-as-of-jan-4. Accessed October 9, 2019. 20. Important Notice: Gabapentin Becomes a Schedule 5 Controlled Substance in Kentucky. https://pharmacy.ky.gov/Documents/Gabapentin%20- %20Schedule%20V%20Controlled%20Substance.pdf. Accessed October 9, 2019. 21. Medical Association of the State of Alabama. Effective Nov. 18: Gabapentin Changed to Schedule V. July 19, 2019 https://alabamamedicine.org/effective-nov-18-gabapentin-changed- to-schedule-v/. Accessed October 9, 2019. 22. Gabapentin will be a Schedule V controlled substance in Tennessee effective July 1, 2018. https://www.tn.gov/content/dam/tn/health/healthprofboards/New%20Statue%20Gabapentin %2006-18.pdf. Accessed October 9, 2019. 23. Controlled Substances Advisory Committee—2019 Legislative Recommendations. https://dopl.utah.gov/csac/csac_annual_report_2018.pdf. Accessed October 9, 2019. 24. Effective Dec 1, Pharmacies, Prescribers, and Wholesalers Must Report Gabapentin to Ohio Automated Rx Reporting System. NLR. https://www.natlawreview.com/article/effective-dec-1- pharmacies-prescribers-and-wholesalers-must-report-gabapentin-to. Published 2016. Accessed June 18, 2019. 25. State of Ohio Board of Pharmacy News. February 2018. https://nabp.pharmacy/wp- content/uploads/2016/06/Ohio-Newsletter-February-2018.pdf. Accessed October 9, 2019. 26. Schifano F, Chiappini S, Corkery JM, Guirguis A. Abuse of Prescription Drugs in the Context of Novel Psychoactive Substances (NPS): A Systematic Review. Brain sciences. 2018;8(4). 27. Schifano F. Misuse and abuse of pregabalin and gabapentin: cause for concern? CNS drugs. 2014;28(6):491-496. 28. Grosshans M, Lemenager T, Vollmert C, et al. Pregabalin abuse among opiate addicted patients. European Journal of Clinical Pharmacology. 2013;69(12):2021-2025. 29. Johanson C-E, Balster RL, Henningfield JE, et al. Risk management and post-marketing surveillance for the abuse of medications acting on the central nervous system: expert panel report. Drug and alcohol dependence. 2009;105 Suppl 1(Suppl 1):S65-S71. 30. McColl S, Sellers EM. Research design strategies to evaluate the impact of formulations on abuse liability. Drug and Alcohol Dependence. 2006;83:S52-S62. 31. Schifano F, Papanti GD, Orsolini L, Corkery JM. The consequences of drug misuse on postmarketing surveillance. Expert Review of Clinical Pharmacology. 2016;9(7):867-871. 32. Systematic Reviews in PubMed and other enhancements. February 21st, 2019 https://news.nnlm.gov/nphco/systematic-reviews-in-pubmed-and-other-enhancements/. Accessed October 14, 2019. 33. Dalhousie University Libraries. http://dal.ca.libguides.com/systematicreviews/searchfilters. Accessed October 22, 2019. 34. The Scottish Intercollegiate Guidelines Network (SIGN) Search Filters. https://www.sign.ac.uk/search-filters.html. Accessed October 14, 2019. 35. Center for Substance Abuse Research (CESAR). http://www.cesar.umd.edu/. Accessed October 9, 2019. 36. Covidence systematic review software, Veritas Health Innovation, Melbourne, Australia. . www.covidence.org. Accessed.

37. Bockbrader HN, Wesche D, Miller R, Chapel S, Janiczek N, Burger P. A Comparison of the Pharmacokinetics and Pharmacodynamics of Pregabalin and Gabapentin. Clinical Pharmacokinetics. 2010;49(10):661-669. 38. Quintero GC. Review about gabapentin misuse, interactions, contraindications and side effects. Journal of experimental pharmacology. 2017;9:13-21. 39. Fischer JH, Ban AN, Rogers SL, Fischer PA, Trudeau VL. Lack of serious toxicity following gabapentin overdose. Neurology. 1994;44(5):982. 40. Häkkinen M, Vuori E, Kalso E, Gergov M, Ojanperä I. Profiles of pregabalin and gabapentin abuse by postmortem toxicology. Forensic Science International. 2014;241:1-6. 41. Chiappini S, Schifano F. A Decade of Gabapentinoid Misuse: An Analysis of the European Medicines Agency’s ‘Suspected Adverse Drug Reactions’ Database. CNS drugs. 2016;30(7):647- 654. 42. Eckhardt K, Ammon S, Hofmann U, Riebe A, Gugeler N, Mikus G. Gabapentin Enhances the Analgesic Effect of Morphine in Healthy Volunteers. Anesthesia & Analgesia. 2000;91(1):185- 191. 43. Lexicomp Online, Gabapentin Enacarbil (Lexi-Drugs), Hudson, Ohio: Wolters Kluwer Clinical Drug Information, Inc.; 2019. Accessed December 2, 2019. 44. Chen C. Meta-analyses of dose-exposure relationships for gabapentin following oral administration of gabapentin and gabapentin enacarbil. European Journal of Clinical Pharmacology. 2013;69(10):1809-1817. 45. Micromedex® (electronic version). IBM Watson Health, Greenwood Village, Colorado, USA. Available at: https://www.micromedexsolutions.com/ (cited: November 20, 2019). 46. Hedegaard H, Bastian BA, Trinidad JP, Spencer M, Warner M. Drugs most frequently involved in drug overdose deaths: United States, 2011–2016. National Vital Statistics Reports; vol 67 no 9. Hyattsville, MD: National Center for Health Statistics. 2018. 47. Gummin DD, Mowry JB, Spyker DA, Brooks DE, Fraser MO, Banner W. 2016 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 34th Annual Report. Clinical toxicology (Philadelphia, Pa). 2017;55(10):1072-1252. 48. Substance Abuse and Mental Health Services Administration (SAMHSA) Drug Abuse Warning Network (DAWN). https://www.samhsa.gov/data/data-we-collect/dawn-drug-abuse-warning- network. Accessed November 20, 2019. 49. Schifano F, D’Offizi S, Piccione M, et al. Is There a Recreational Misuse Potential for Pregabalin? Analysis of Anecdotal Online Reports in Comparison with Related Gabapentin and Clonazepam Data. Psychotherapy and Psychosomatics. 2011;80(2):118-122. 50. Calandre EP, Rico-Villademoros F, Slim M. Alpha2delta ligands, gabapentin, pregabalin and mirogabalin: a review of their clinical pharmacology and therapeutic use. Expert Rev Neurother. 2016;16(11):1263-1277. 51. Gomes T, Juurlink DN, Antoniou T, Mamdani MM, Paterson JM, van den Brink W. Gabapentin, opioids, and the risk of opioid-related death: A population-based nested case-control study. PLoS medicine. 2017;14(10):e1002396. 52. Hamer AM ea. Gabapentin use in a managed medicaid population. JMCP. 2002;8(4):266-271. 53. Radley DC ea. Off-label prescribing among office-based physicians. Arch Intern Med. 2006;166(9):1021-1026. 54. Berlin RK, Butler PM, Perloff MD. Gabapentin Therapy in Psychiatric Disorders: A Systematic Review. The primary care companion for CNS disorders. 2015;17(5):330. 55. David AG. Pharmacological Treatment of Cannabis-Related Disorders: A Narrative Review. Current Pharmaceutical Design. 2016;22(42):6409-6419.

56. Karila L, Weinstein A, Aubin HJ, Benyamina A, Reynaud M, Batki SL. Pharmacological approaches to methamphetamine dependence: a focused review. British journal of clinical pharmacology. 2010;69(6):578-592. 57. Laprevote V, Schwan R, Schwitzer T, Rolland B, Thome J. Is there a place for off-label pharmacotherapy in cannabis use disorder? A review on efficacy and safety. Current pharmaceutical design. 2015;21(23):3298-3305. 58. Marshall K, Gowing L, Ali R, Le Foll B. Pharmacotherapies for cannabis dependence. The Cochrane database of systematic reviews. 2014;12(12):CD008940-CD008940. 59. Minozzi S, Cinquini M, Amato L, et al. Anticonvulsants for cocaine dependence. Cochrane Database of Systematic Reviews. 2015;4(4):CD006754. 60. Nielsen S, Gowing L, Sabioni P, Le Foll B. Pharmacotherapies for cannabis dependence. The Cochrane database of systematic reviews. 2019;1:CD008940. 61. Zhand N, Milin R. What do we know about the pharmacotheraputic management of insomnia in cannabis withdrawal: A systematic review. The American journal on addictions. 2018;27(6):453- 464. 62. Walther L, Gantner A, Heinz A, Majić T. Evidence-based Treatment Options in Cannabis Dependency. Deutsches Arzteblatt international. 2016;113(39):653-659. 63. Reus VI, Fochtmann LJ, Bukstein O, et al. The American Psychiatric Association Practice Guideline for the Pharmacological Treatment of Patients With Alcohol Use Disorder. The American journal of psychiatry. 2018;175(1):86-90. 64. US Department of Veterans Affairs/Department of Defense (VA/DoD). VA/DoD clinical practice guideline for the management of substance use disorders. http://www.healthquality.va.gov/guidelines/MH/sud/VADoDSUDCPGRevised22216.pdf. Published December 2015. Accessed August 2016. 65. Gibson P, Wang G, McGarvey L, et al. Treatment of Unexplained Chronic Cough: CHEST Guideline and Expert Panel Report. Chest. 2016;149(1):27-44. 66. Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015;14(2):162-173. 67. Attal N, Cruccu G, Baron R, et al. EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur J Neurol. 2010;17(9):1113-e1188. 68. Devlin JW, Skrobik Y, Gelinas C, et al. Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU. Crit Care Med. 2018;46(9):e825-e873. 69. National Institute for Health and Care Excellence. Neuropathic pain in adults: pharmacological management in non-specialist settings. https://www.nice.org.uk/guidance/CG173. Published November 2013. Updated April 2018. 70. Bril V, England J, Franklin GM, et al. Evidence-based guideline: Treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology. 2011;76(20):1758-1765. 71. Pop-Busui R, Boulton AJM, Feldman EL, et al. Diabetic Neuropathy: A Position Statement by the American Diabetes Association. Diabetes Care. 2017;40(1):136. 72. Chou R, Gordon DB, de Leon-Casasola OA, et al. Management of Postoperative Pain: A Clinical Practice Guideline From the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists' Committee on Regional Anesthesia, Executive Committee, and Administrative Council. The Journal of Pain. 2016;17(2):131-157.

73. Weisshaar E, Szepietowski JC, Darsow U, et al. European guideline on chronic pruritus. Acta Derm Venereol. 2012;92(5):563-581. 74. Cobin RH, Goodman NF. AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY POSITION STATEMENT ON MENOPAUSE–2017 UPDATE. Endocrine Practice. 2017;23(7):869-880. 75. Stuenkel CA, Davis SR, Gompel A, et al. Treatment of Symptoms of the Menopause: An Endocrine Society Clinical Practice Guideline. The Journal of Clinical Endocrinology & Metabolism. 2015;100(11):3975-4011. 76. Nonhormonal management of menopause-associated vasomotor symptoms: 2015 position statement of The North American Menopause Society. Menopause. 2015;22(11):1155-1172; quiz 1173-1154. 77. Runowicz CD, Leach CR, Henry NL, et al. American Cancer Society/American Society of Clinical Oncology Breast Cancer Survivorship Care Guideline. Journal of Clinical Oncology. 2015;34(6):611-635. 78. Aurora RN, Kristo DA, Bista SR, et al. The Treatment of Restless Legs Syndrome and Periodic Limb Movement Disorder in Adults—An Update for 2012: Practice Parameters with an Evidence- Based Systematic Review and Meta-Analyses: An American Academy of Sleep Medicine Clinical Practice Guideline. Sleep. 2012;35(8):1039-1062. 79. Garcia-Borreguero D, Ferini-Strambi L, Kohnen R, et al. European guidelines on management of restless legs syndrome: report of a joint task force by the European Federation of Neurological Societies, the European Neurological Society and the European Sleep Research Society. European Journal of Neurology. 2012;19(11):1385-1396. 80. Garcia-Borreguero D, Silber MH, Winkelman JW, et al. Guidelines for the first-line treatment of restless legs syndrome/Willis–Ekbom disease, prevention and treatment of dopaminergic augmentation: a combined task force of the IRLSSG, EURLSSG, and the RLS-foundation. Sleep Medicine. 2016;21:1-11. 81. Picchietti DL, Hensley JG, Bainbridge JL, et al. Consensus clinical practice guidelines for the diagnosis and treatment of restless legs syndrome/Willis-Ekbom disease during pregnancy and lactation. Sleep Med Rev. 2015;22:64-77. 82. Marsden J, White M, Annand F, et al. Medicines associated with dependence or withdrawal: a mixed-methods public health review and national database study in England. The lancet Psychiatry. 2019. 83. Juenke JM, Brown PI, Johnson-Davis KL, McMillin GA. Simultaneous quantification of levetiracetam and gabapentin in plasma by ultra-pressure liquid chromatography coupled with tandem mass spectrometry detection. Ther Drug Monit. 2011;33(2):209-213. 84. Filipetto FA, Zipp CP, Coren JS. Potential for Pregabalin Abuse or Diversion After Past Drug- Seeking Behavior. The Journal of the American Osteopathic Association. 2010;110(10):605-607. 85. Voichita Bar A. Gabapentin for the Treatment of Cancer-Related Pain Syndromes. Reviews on Recent Clinical Trials. 2010;5(3):174-178. 86. Jankovic SM, Dostic M. Choice of antiepileptic drugs for the elderly: possible drug interactions and adverse effects. Expert Opinion on Drug Metabolism & Toxicology. 2012;8(1):81-91. 87. Díaz RASP, Sancho JM, Serratosa JM, PhD. Antiepileptic Drug Interactions. The Neurologist. 2008;14(6):S55-S65. 88. Reeves RR, Burke RS. Abuse of combinations of gabapentin and quetiapine. The primary care companion for CNS disorders. 2014;16(5):10.4088/PCC.4014l01660. 89. Victorri-Vigneau C, Guerlais M, Jolliet P. Abuse, dependency and withdrawal with gabapentin: a first case report. Pharmacopsychiatry. 2007;40(1):43-44.

90. Smith BH, Higgins C, Baldacchino A, Kidd B, Bannister J. Substance misuse of gabapentin. The British journal of general practice : the journal of the Royal College of General Practitioners. 2012;62(601):406-407. 91. Roy R. Reeves, D.O., Ph.D. , and, Mark E. Ladner, M.D. Potentiation of the Effect of Buprenorphine/Naloxone With Gabapentin or Quetiapine. American Journal of Psychiatry. 2014;171(6):691-691. 92. Grotle M, Foster NE, Dunn KM, Croft P. Are prognostic indicators for poor outcome different for acute and chronic low back pain consulters in primary care? Pain. 2010;151(3):790-797. 93. Public Health England, NHS England. Advice for prescribers on the risk of the misuse of pregabalin and gabapentin. December, 2014. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_dat a/file/385791/PHE-NHS_England_pregabalin_and_gabapentin_advice_Dec_2014.pdf. Accessed December 4, 2019. 94. Smith RV, Lofwall MR, Havens JR. Abuse and diversion of gabapentin among nonmedical prescription opioid users in Appalachian Kentucky. The American journal of psychiatry. 2015;172(5):487-488. 95. Kapil V, Green JL, Le Lait M-C, Wood DM, Dargan PI. Misuse of the γ-aminobutyric acid analogues baclofen, gabapentin and pregabalin in the UK. British journal of clinical pharmacology. 2014;78(1):190-191. 96. VA/DoD Clinical Practice Guideline for the Management of Substance Use Disorders, Department of Veterans Affairs and Department of Defense (2015). 97. Bastiaens L, Galus J, Mazur C. Abuse of Gabapentin is Associated with Opioid Addiction. Psychiatr Q. 2016;87(4):763-767. 98. Baird CRW, Fox P, Colvin LA. Gabapentinoid abuse in order to potentiate the effect of methadone: A survey among substance misusers. European Addiction Research. 2014;20(3):115- 118. 99. Mackey TK, Nayyar G. Digital danger: a review of the global public health, patient safety and cybersecurity threats posed by illicit online pharmacies. Br Med Bull. 2016;118(1):110-126. 100. Schifano F, Orsolini L, Duccio Papanti G, Corkery JM. Novel psychoactive substances of interest for psychiatry. World Psychiatry. 2015;14(1):15-26. 101. Orsolini L, Papanti GD, Francesconi G, Schifano F. Mind Navigators of Chemicals' Experimenters? A Web-Based Description of E-Psychonauts. Cyberpsychology, Behavior, and Social Networking. 2015;18(5):296-300. 102. Greater use of gabapentinoids in intentional drug overdose. Reactions Weekly. 2018;1684(1):5- 5. 103. Wilens T, Zulauf C, Ryland D, Carrellas N, Catalina-Wellington I. Prescription medication misuse among opioid dependent patients seeking inpatient detoxification. American Journal on Addictions. 2015;24(2):173-177. 104. Wills B, Reynolds P, Chu E, et al. Clinical outcomes in newer anticonvulsant overdose: a poison center observational study. J Med Toxicol. 2014;10(3):254-260. 105. Lyndon A, Audrey S, Wells C, et al. Risk to heroin users of polydrug use of pregabalin or gabapentin. Addiction (Abingdon, England). 2017;112(9):1580-1589. 106. Klein-Schwartz W, Shepherd JG, Gorman S, Dahl B. Characterization of gabapentin overdose using a poison center case series. J Toxicol Clin Toxicol. 2003;41(1):11-15. 107. Barrueto F, Jr., Green J, Howland MA, Hoffman RS, Nelson LS. Gabapentin withdrawal presenting as status epilepticus. J Toxicol Clin Toxicol. 2002;40(7):925-928. 108. Cantrell FL, Mena O, Gary RD, McIntyre IM. An acute gabapentin fatality: a case report with postmortem concentrations. Int J Legal Med. 2015;129(4):771-775.

109. Rohman L, Hebron A. Acute dystonic reaction caused by gabapentin. J Emerg Med. 2014;46(3):e89. 110. Markowitz JS, Finkenbine R, Myrick H, King L, Carson WH. Gabapentin abuse in a cocaine user: implications for treatment? J Clin Psychopharmacol. 1997;17(5):423-424. 111. Peterson BL. Prevalence of gabapentin in impaired driving cases in Washington State in 2003- 2007. J Anal Toxicol. 2009;33(8):545-549. 112. Cossmann JC, Scherbaum N, Bonnet U. Substance addiction in old age: A cross-sectional study in a German hospital. GeroPsych: The Journal of Gerontopsychology and Geriatric Psychiatry. 2016;29(1):17-27. 113. Schulz M, Iwersen-Bergmann S, Andresen H, Schmoldt A. Therapeutic and toxic blood concentrations of nearly 1,000 drugs and other xenobiotics. Crit Care. 2012;16(4):R136. 114. Spiller HA, Dunaway MD, Cutino L. Massive gabapentin and presumptive quetiapine overdose. Vet Hum Toxicol. 2002;44(4):243-244. 115. Koschny R, Lutz M, Seckinger J, Schwenger V, Stremmel W, Eisenbach C. Extracorporeal life support and plasmapheresis in a case of severe polyintoxication. J Emerg Med. 2014;47(5):527- 531. 116. Schauer SG, Varney SM. Gabapentin overdose in a military beneficiary. Mil Med. 2013;178(1):e133-135. 117. Verma A, St Clair EW, Radtke RA. A case of sustained massive gabapentin overdose without serious side effects. Ther Drug Monit. 1999;21(6):615-617. 118. Moore KA, Levine B, Fowler D. A fatality involving metaxalone. Forensic Sci Int. 2005;149(2- 3):249-251. 119. Middleton O. Suicide by Gabapentin Overdose. Journal of forensic sciences. 2011;56(5):1373- 1375. 120. Mowry JB, Spyker DA, Cantilena LR, Jr., Bailey JE, Ford M. 2012 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 30th Annual Report. Clinical toxicology (Philadelphia, Pa). 2013;51(10):949-1229. 121. Mowry JB, Spyker DA, Cantilena LR, Jr., McMillan N, Ford M. 2013 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 31st Annual Report. Clinical toxicology (Philadelphia, Pa). 2014;52(10):1032-1283. 122. Mowry JB, Spyker DA, Brooks DE, McMillan N, Schauben JL. 2014 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 32nd Annual Report. Clinical toxicology (Philadelphia, Pa). 2015;53(10):962-1147. 123. Mowry JB, Spyker DA, Brooks DE, Zimmerman A, Schauben JL. 2015 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 33rd Annual Report. Clinical toxicology (Philadelphia, Pa). 2016;54(10):924-1109. 124. Daly C, Griffin E, Ashcroft DM, Webb RT, Perry IJ, Arensman E. Intentional Drug Overdose Involving Pregabalin and Gabapentin: Findings from the National Self-Harm Registry Ireland, 2007–2015. Clinical Drug Investigation. 2018;38(4):373-380. 125. Erowid. Experiences. Available online: https://erowid.org/experiences/ (accessed on 16 January 2018). 126. Reccoppa L, Malcolm R, Ware M. Gabapentin Abuse in Inmates with Prior History of Cocaine Dependence. The American Journal on Addictions. 2004;13(3):321-323. 127. Lile JA, Wesley MJ, Kelly TH, Hays LR. Separate and combined effects of gabapentin and [INCREMENT]9-tetrahydrocannabinol in humans discriminating [INCREMENT]9- tetrahydrocannabinol. Behav Pharmacol. 2016;27(2-3 Spec Issue):215-224. 128. Pittenger C, Desan PH. Gabapentin abuse, and delirium tremens upon gabapentin withdrawal. J Clin Psychiatry. 2007;68(3):483-484.

129. Kruszewski SP, Paczynski RP, Kahn DA. Gabapentin-Induced Delirium and Dependence. Journal of Psychiatric Practice®. 2009;15(4):314-319. 130. Satish R, Kandasamy A, Jayarajan D, Benegal V. Gabapentin dependence in a patient with opioid dependence syndrome. J Neuropsychiatry Clin Neurosci. 2015;27(1):e64. 131. Jonsson B, Backman E, Salmonson H, Hojer J. Injection of crushed tablets--a prospective observational study. Clinical toxicology (Philadelphia, Pa). 2014;52(9):982-983. 132. Fernandez MC, Walter FG, Petersen LR, Walkotte SM. Gabapentin, valproic acid, and ethanol intoxication: elevated blood levels with mild clinical effects. J Toxicol Clin Toxicol. 1996;34(4):437-439. 133. Stopforth J. Overdose with gabapentin and lamotrigine. S Afr Med J. 1997;87(10):1388. 134. Rasimas JJ, Burkhart KK. Cardiac conduction disturbances after an overdose of nefazodone and gabapentin. Am J Emerg Med. 2006;24(7):886-888.